PDE1 inhibitor compounds

ABSTRACT

The present invention relates to (1- or 2- and/or 5 and/or 7-substituted)-(3-oxy)-(4H,4-imino, 4-thioxo or 4-oxo)-pyrazolo[3,4-d]pyrimidin-6-ones, e.g., a compound of formula II as described below, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them. Of particular interest are novel compounds useful as inhibitors of phosphodiesterase 1 (PDE1), e.g., in the treatment of diseases involving disorders of the dopamine D1 receptor intracellular pathway, such as Parkinson&#39;s disease, depression, narcolepsy, damage to cognitive function, e.g., in schizophrenia, or disorders that may be ameliorated through enhanced progesterone-signaling pathway, e.g., female sexual dysfunction.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a United States Application under 35 U.S.C. 371claiming benefit of PCT Application No. PCT/US2011/038544, filed on May31, 2011, which claims priority from U.S. Provisional Application No.61/349,959, filed May 31, 2010, the contents of each of which are herebyincorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to (1- or 2- and/or 5 and/or7-substituted)-(3-oxy)-(4H,4-imino, 4-thioxo or4-oxo)-pyrazolo[3,4-d]pyrimidin-6-ones, e.g., a compound of formula IIas described below, processes for their production, their use aspharmaceuticals and pharmaceutical compositions comprising them. Ofparticular interest are novel compounds useful as inhibitors ofphosphodiesterase 1 (PDE1), e.g., in the treatment of diseases involvingdisorders of the dopamine D1 receptor intracellular pathway, such asParkinson's disease, depression, narcolepsy, damage to cognitivefunction, e.g., in schizophrenia, or disorders that may be amelioratedthrough enhanced progesterone-signaling pathway, e.g., female sexualdysfunction.

BACKGROUND OF THE INVENTION

Eleven families of phosphodiesterases (PDEs) have been identified butonly PDEs in Family I, the Ca²⁺-calmodulin-dependent phosphodiesterases(CaM-PDEs), have been shown to mediate both the calcium and cyclicnucleotide (e.g. cAMP and cGMP) signaling pathways. The three knownCaM-PDE genes, PDE1A, PDE1B, and PDE1C, are all expressed in centralnervous system tissue. PDE1A is expressed throughout the brain withhigher levels of expression in the CA1 to CA3 layers of the hippocampusand cerebellum and at a low level in the striatum. PDE1A is alsoexpressed in the lung and heart. PDE1B is predominately expressed in thestriatum, dentate gyrus, olfactory tract and cerebellum, and itsexpression correlates with brain regions having high levels ofdopaminergic innervation. Although PDE1B is primarily expressed in thecentral nervous system, it may be detected in the heart. PDE1C isprimarily expressed in olfactory epithelium, cerebellar granule cells,and striatum. PDE1C is also expressed in the heart and vascular smoothmuscle.

Cyclic nucleotide phosphodiesterases decrease intracellular cAMP andcGMP signaling by hydrolyzing these cyclic nucleotides to theirrespective inactive 5′-monophosphates (5′AMP and 5′GMP). CaM-PDEs play acritical role in mediating signal transduction in brain cells,particularly within an area of the brain known as the basal ganglia orstriatum. For example, NMDA-type glutamate receptor activation and/ordopamine D2 receptor activation result in increased intracellularcalcium concentrations, leading to activation of effectors such ascalmodulin-dependent kinase II (CaMKII) and calcineurin and toactivation of CaM-PDEs, resulting in reduced cAMP and cGMP. Dopamine D1receptor activation, on the other hand, leads to activation ofnucleotide cyclases, resulting in increased cAMP and cGMP. These cyclicnucleotides in turn activate protein kinase A (PKA; cAMP-dependentprotein kinase) and/or protein kinase G (PKG; cGMP-dependent proteinkinase) that phosphorylate downstream signal transduction pathwayelements such as DARPP-32 (dopamine and cAMP-regulated phosphoprotein)and cAMP responsive element binding protein (CREB). PhosphorylatedDARPP-32 in turn inhibits the activity of protein phosphates-1 (PP-1),thereby increasing the state of phosphorylation of substrate proteinssuch as progesterone receptor (PR), leading to induction of physiologicresponses. Studies in rodents have suggested that inducing cAMP and cGMPsynthesis through activation of dopamine D1 or progesterone receptorenhances progesterone signaling associated with various physiologicalresponses, including the lordosis response associated with receptivityto mating in some rodents. See Mani, et al., Science (2000) 287: 1053,the contents of which are incorporated herein by reference.

CaM-PDEs can therefore affect dopamine-regulated and other intracellularsignaling pathways in the basal ganglia (striatum), including but notlimited to nitric oxide, noradrenergic, neurotensin, CCK, VIP,serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA,acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor,natriuretic peptide (e.g., ANP, BNP, CNP), DARPP-32, and endorphinintracellular signaling pathways.

Phosphodiesterase (PDE) activity, in particular, phosphodiesterase 1(PDE1) activity, functions in brain tissue as a regulator of locomotoractivity and learning and memory. PDE1 is a therapeutic target forregulation of intracellular signaling pathways, preferably in thenervous system, including but not limited to a dopamine D1 receptor,dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK,VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA,acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor,natriuretic peptide (e.g., ANP, BNP, CNP), endorphin intracellularsignaling pathway and progesterone signaling pathway. For example,inhibition of PDE1B should act to potentiate the effect of a dopamine D1agonist by protecting cGMP and cAMP from degradation, and shouldsimilarly inhibit dopamine D2 receptor signaling pathways, by inhibitingPDE1 activity. Chronic elevation in intracellular calcium levels islinked to cell death in numerous disorders, particularly inneurodegerative diseases such as Alzheimer's, Parkinson's andHuntington's Diseases and in disorders of the circulatory system leadingto stroke and myocardial infarction. PDE1 inhibitors are thereforepotentially useful in diseases characterized by reduced dopamine D1receptor signaling activity, such as Parkinson's disease, restless legsyndrome, depression, narcolepsy and cognitive impairment. PDE1inhibitors are also useful in diseases that may be alleviated by theenhancement of progesterone-signaling such as female sexual dysfunction.

There is thus a need for compounds that selectively inhibit PDE1activity, especially PDE1A and/or PDE1B activity.

SUMMARY OF THE INVENTION

The invention provides (1- or 2- and/or 5 and/or7-substituted)-(3-oxy)-(4H,4-imino, 4-thioxo or4-oxo)-pyrazolo[3,4-d]pyrimidin-6-ones, e.g., a compound of formula II:

wherein

(i) Q is —C(═O)—, —C(═S)—, —C(═N(R₆))— or —C(R₁₄)(R₁₅)—;

(ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);

(iii) R₂ is

-   -   H,    -   C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or        2,2-dimethylpropyl) wherein said alkyl group is optionally        substituted with one or more halo (e.g., fluoro) or hydroxy        (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or        3-hydroxy-2-methylpropyl),    -   haloC₁₋₆alkyl (e.g., trifluoromethyl or 2,2,2-trifluoroethyl),    -   N(R₁₄)(R₁₅)—C₁₋₆alkyl (e.g., 2-(dimethylamino)ethyl or        2-aminopropyl),    -   arylC₀₋₆alkyl (e.g., phenyl or benzyl), wherein said aryl is        optionally substituted with one or more C₁₋₆alkoxy, for example,        C₁₋₆alkoxyarylC₀₋₆alkyl (e.g., 4-methoxybenzyl),    -   heteroarylC₀₋₆alkyl (e.g., pyridinylmethyl), wherein said        heteroaryl is optionally substituted with one or more C₁₋₆alkoxy        (e.g., C₁₋₆alkoxyheteroarylC₁₋₆alkyl);    -   -G-J wherein G is a single bond or C₁₋₆alkylene (e.g.,        methylene) and J is C₃₋₈cycloalkyl or heteroC₃₋₈cycloalkyl        (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein        the cycloalkyl and heterocycloalkyl group are optionally        substituted with one or more C₁₋₆alkyl or amino, for example,        -   —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g., —C₀₋₄alkyl-cyclopentyl,            —C₀₋₄alkyl-cyclohexyl or —C₀₋₄alkyl-cyclopropyl), wherein            said cycloalkyl is optionally substituted with one or more            C₁₋₆alkyl or amino (for example, 2-aminocyclopentyl or            2-aminocyclohexyl),        -   —C₀₋₄alkyl-C₃₋₈heterocycloalkyl (e.g.,            —C₀₋₄alkyl-pyrrolidinyl, for example,            —C₀₋₄alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is            optionally substituted with C₁₋₆alkyl (e.g., methyl), for            example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl,            1-methyl-pyrrolindin-2-yl-methyl or            1-methyl-pyrrolindin-3-yl-methyl);    -   (iv) R₃ is        -   1) -D-E-F wherein:            -   D is a single bond, C₁₋₆alkylene (e.g., methylene), or                arylC₁₋₆alkylene (e.g., benzylene or —CH₂C₆H₄—);            -   E is                -   a single bond,                -   C₁₋₄alkylene (e.g., methylene, ethynylene,                    prop-2-yn-1-ylene),                -   C₀₋₄alkylarylene (e.g., phenylene or —C₆H₄—,                    -benzylene- or —CH₂C₆H₄—), wherein the arylene group                    is optionally substituted with halo (e.g., Cl or F),                -   heteroarylene (e.g., pyridinylene or                    pyrimidinylene),                -   aminoC₁₋₆alkylene (e.g., —CH₂N(H)—),                -   amino (e.g., —N(H)—);                -   C₃₋₈cycloalkylene optionally containing one or more                    heteroatom selected from N or O (e.g.,                    piperidinylene),            -   F is                -   H,                -   halo (e.g., F, Br, Cl),                -   C₁₋₆alkyl (e.g., isopropyl or isobutyl),                -   haloC₁₋₆alkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl),                -   C₃₋₈cycloalkyl optionally containing one or more                    atom selected from a group consisting of N, S or O                    (e.g., cyclopentyl, cyclohexyl, piperidinyl,                    pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or                    morpholinyl), and optionally substituted with one or                    more C₁₋₆alkyl (e.g., methyl or isopropyl), for                    example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl,                    pyrrolidin-2-yl, piperidin-2-yl,                    1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl,                -   heteroaryl optionally substituted with one or more                    C₁₋₆alkyl, halo (e.g., fluoro) or haloC₁₋₆alkyl                    (e.g., pyridyl (for example, pyrid-2-yl),                    pyrimidinyl (for example, pyrimidin-2-yl),                    thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl),                    diazolyl (e.g., pyrazolyl (for example,                    pyrazol-1-yl) or imidazolyl (for example,                    imidazol-1-yl, 4-methylimidazolyl,                    1-methylimidazol-2-yl)), triazolyl (e.g.,                    1,2,4-triazol-1-yl), tetrazolyl (e.g.,                    tetrazol-5-yl),                -   C₁₋₆alkyloxadiazolyl (e.g.,                    5-methyl-1,2,4-oxadiazolyl);                -   C₁₋₆alkoxy,                -   —O-haloC₁₋₆alkyl (e.g., —O—CF₃),                -   C₁₋₆alkylsulfonyl (for example, methylsulfonyl or                    —S(O)₂CH₃),                -   —C(O)—R₁₃, wherein R₁₃ is —N(R₁₄)(R₁₅), C₁₋₆alkyl                    (e.g., methyl), —OC₁₋₆alkyl (e.g., —OCH₃),                    haloC₁₋₆alkyl (trifluoromethyl), aryl (e.g.,                    phenyl), or heteroaryl;                -   —N(R₁₄)(R₁₅);            -   or        -   2) a substituted heteroarylC₁₋₆alkyl, e.g., substituted with            haloC₁₋₆alkyl;            -   or        -   3) attached to one of the nitrogens on the pyrazolo portion            of Formula II and is a moiety of Formula A

-   -   -   -   wherein:                -   X, Y and Z are, independently, N or C,                -   R₈, R₉, R₁₁ and R₁₂ are independently H or halogen                    (e.g., Cl or F); and                -   R₁₀ is                -    halogen (e.g., fluoro or chloro),                -    C₁₋₆alkyl,                -    C₃₋₈cycloalkyl,                -    heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl or                    piperidinyl),                -    haloC₁₋₆alkyl (e.g., trifluoromethyl),                -    aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl,                    (for example, pyrid-2-yl) or e.g., thiadiazolyl (for                    example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g.,                    pyrazolyl (for example, pyrazol-1-yl) or imidazolyl                    (for example, imidazol-1-yl)), triazolyl (e.g.,                    1,2,4-triazol-1-yl), tetrazolyl (e.g.,                    tetrazol-5-yl), C₁₋₆alkyloxadiazolyl (e.g.,                    5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,                    pyrazol-1-yl),                -    wherein said aryl, heteroaryl, cycloalkyl or                    heterocycloalkyl is optionally substituted with one                    or more C₁₋₆alkyl (e.g., methyl), halogen (e.g.,                    chloro or fluoro), haloC₁₋₆alkyl (e.g.,                    trifluoromethyl), hydroxy, carboxy, —SH, or an                    additional aryl or heteroaryl (e.g., biphenyl or                    pyridylphenyl),                -    C₁₋₆alkyl sulfonyl (e.g., methyl sulfonyl),                -    arylcarbonyl (e.g., benzoyl),                -    heteroarylcarbonyl,                -    C₁₋₆alkoxycarbonyl, (e.g., methoxycarbonyl),                -    Aminocarbonyl,                -    —N(R₁₄)(R₁₅);                -    preferably R₁₀ is phenyl, pyridyl, piperidinyl or                    pyrrolidinyl optionally substituted with the                    substituents previously defined, e.g. optionally                    substituted with halo or alkyl;                -   provided that when X, Y or Z is nitrogen, R₈, R₉ or                    R₁₀, respectively, is not present;

    -   (v) R₄ is:        -   C₁₋₆alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl),        -   C₃₋₈cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   C₃₋₈heterocycloalkyl (e.g., pyrrolidinyl (for example            pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for            example, piperidin-1-yl), morpholinyl),        -   —C₀₋₆alkylaryl (e.g., phenyl or benzyl) or        -   —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or            pyrazol-3-yl)        -   wherein said aryl or heteroaryl is optionally substituted            with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g.,            4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or another aryl            group (e.g., biphenyl-4-ylmethyl);

    -   (vi) R₆ is H, C₁₋₆alkyl (e.g., methyl or ethyl) or        C₃₋₈cycloalkyl;

    -   (vii) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl,        in free or salt form.

In a particular embodiment, the invention further provides a compound ofFormula II as follows:

-   -   2.1 Formula II or 2.1, wherein Q is —C(═O)—, —C(═S)—,        —C(═N(R₆))— or —C(R₁₄)(R₁₅)—;    -   2.2 Formula II or 2.1, wherein Q is —C(═O)—;    -   2.3 Formula II or 2.1, wherein Q is —C(═S)—;    -   2.4 Formula II or 2.1, wherein Q is —C(═N(R₆))—;    -   2.5 Formula II, wherein Q is —C(R₁₄)(R₁₅)—;    -   2.6 Formula II or any of 2.1-2.5, wherein R₁ is H or C₁₋₆alkyl        (e.g., methyl or ethyl);    -   2.7 Formula II or any of 2.1-2.6, wherein R₁ is H,    -   2.8 Formula II or any of 2.1-2.6, wherein R₁ is C₁₋₆alkyl (e.g.,        methyl or ethyl);    -   2.9 Formula II or any of 2.5-2.8, wherein R₂ is:        -   H,        -   C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or            2,2-dimethylpropyl) wherein said alkyl group is optionally            substituted with one or more halo (e.g., fluoro) or hydroxy            (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or            3-hydroxy-2-methylpropyl),        -   haloC₁₋₆alkyl (e.g., trifluoromethyl or            2,2,2-trifluoroethyl),        -   N(R₁₄)(R₁₅)—C₁₋₆alkyl (e.g., 2-(dimethylamino)ethyl or            2-aminopropyl),        -   arylC₀₋₆alkyl (e.g., phenyl or benzyl), wherein said aryl is            optionally substituted with one or more C₁₋₆alkoxy, for            example, C₁₋₆alkoxyarylC₀₋₆alkyl (e.g., 4-methoxybenzyl),        -   heteroarylC₀₋₆alkyl (e.g., pyridinylmethyl), wherein said            heteroaryl is optionally substituted with one or more            C₁₋₆alkoxy (e.g., C₁₋₆alkoxyheteroarylC₁₋₆alkyl);        -   -G-J wherein G is a single bond or C₁₋₆alkylene (e.g.,            methylene) and J is C₃₋₈cycloalkyl or heteroC₃₋₈cycloalkyl            (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl)            wherein the cycloalkyl and heterocycloalkyl group are            optionally substituted with one or more C₁₋₆alkyl or amino,            for example,            -   —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g., —C₀₋₄alkyl-cyclopentyl,                —C₀₋₄alkyl-cyclohexyl or —C₀₋₄alkyl-cyclopropyl),                wherein said cycloalkyl is optionally substituted with                one or more C₁₋₆alkyl or amino (for example,                2-aminocyclopentyl or 2-aminocyclohexyl),            -   —C₀₋₄alkyl-C₃₋₈heterocycloalkyl (e.g.,                —C₀₋₄alkyl-pyrrolidinyl, for example,                —C₀₋₄alkylpyrrolidin-3-yl) wherein said heterocycloalkyl                is optionally substituted with C₁₋₆alkyl (e.g., methyl),                for example, 1-methylpyrrolidin-3-yl,                1-methyl-pyrrolindin-2-yl,                1-methyl-pyrrolindin-2-yl-methyl or                1-methyl-pyrrolindin-3-yl-methyl);    -   2.10 Formula II or any of 2.5-2.9, wherein R₂ is:        -   C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or            2,2-dimethylpropyl) wherein said alkyl group is optionally            substituted with one or more halo (e.g., fluoro) or hydroxy            (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or            3-hydroxy-2-methylpropyl),        -   haloC₁₋₆alkyl (e.g., trifluoromethyl or            2,2,2-trifluoroethyl),        -   N(R₁₄)(R₁₅)—C₁₋₆alkyl (e.g., 2-(dimethylamino)ethyl or            2-aminopropyl),        -   arylC₀₋₆alkyl (e.g., phenyl or benzyl), wherein said aryl is            optionally substituted with one or more C₁₋₆alkoxy, for            example, C₁₋₆alkoxyarylC₀₋₆alkyl (e.g., 4-methoxybenzyl),        -   heteroarylC₀₋₆alkyl (e.g., pyridinylmethyl), wherein said            heteroaryl is optionally substituted with one or more            C₁₋₆alkoxy (e.g., C₁₋₆alkoxyheteroarylC₁₋₆alkyl);        -   -G-J wherein G is a single bond or C₁₋₆alkylene (e.g.,            methylene) and J is C₃₋₈cycloalkyl or heteroC₃₋₈cycloalkyl            (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl)            wherein the cycloalkyl and heterocycloalkyl group are            optionally substituted with one or more C₁₋₆alkyl or amino,            for example,        -   —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g., —C₀₋₄alkyl-cyclopentyl,            —C₀₋₄alkyl-cyclohexyl or —C₀₋₄alkyl-cyclopropyl), wherein            said cycloalkyl is optionally substituted with one or more            C₁₋₆alkyl or amino (for example, 2-aminocyclopentyl or            2-aminocyclohexyl),        -   —C₀₋₄alkyl-C₃₋₈heterocycloalkyl (e.g.,            —C₀₋₄alkyl-pyrrolidinyl, for example,            —C₀₋₄alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is            optionally substituted with C₁₋₆alkyl (e.g., methyl), for            example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl,            1-methyl-pyrrolindin-2-yl-methyl or            1-methyl-pyrrolindin-3-yl-methyl);    -   2.11 Formula II or any of 2.5-2.9, wherein R₂ is H,    -   2.12 Formula II or any of 2.5-2.10, wherein R₂ is C₁₋₆alkyl        (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl)        wherein said alkyl group is optionally substituted with one or        more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC₁₋₆alkyl, for        example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl);    -   2.13 Formula II or any of 2.5-2.10, wherein R₂ is haloC₁₋₆alkyl        (e.g., trifluoromethyl or 2,2,2-trifluoroethyl);    -   2.14 Formula II or any of 2.5-2.10, wherein R₂ is        N(R₁₄)(R₁₅)—C₁₋₆alkyl (e.g., 2-(dimethylamino)ethyl,        2-aminopropyl);    -   2.15 Formula II or any of 2.5-2.10, wherein R₂ is arylC₀₋₆alkyl        (e.g., phenyl or benzyl), wherein said aryl is optionally        substituted with one or more C₁₋₆alkoxy, for example,        C₁₋₆alkoxyarylC₀₋₆alkyl (e.g., 4-methoxybenzyl);    -   2.16 Formula II or any of 2.5-2.10, wherein R₂ is        heteroarylC₀₋₆alkyl (e.g., pyridinylmethyl), wherein said        heteroaryl is optionally substituted with one or more C₁₋₆alkoxy        (e.g., C₁₋₆alkoxyheteroarylC₁₋₆alkyl);    -   2.17 Formula II or any of 2.5-2.10, wherein R₂ is -G-J wherein G        is a single bond or C₁₋₆alkylene (e.g., methylene) and J is        C₃₋₈cycloalkyl or heteroC₃₋₈cycloalkyl (e.g., oxetan-2-yl,        pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the cycloalkyl and        heterocycloalkyl group are optionally substituted with one or        more C₁₋₆alkyl or amino, for example:        -   —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g., —C₀₋₄alkyl-cyclopentyl,            —C₀₋₄alkyl-cyclohexyl or —C₀₋₄alkyl-cyclopropyl), wherein            said cycloalkyl is optionally substituted with one or more            C₁₋₆alkyl or amino (for example, 2-aminocyclopentyl or            2-aminocyclohexyl),        -   —C₀₋₄alkyl-C₃₋₈heterocycloalkyl (e.g.,            —C₀₋₄alkyl-pyrrolidinyl, for example,            —C₀₋₄alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is            optionally substituted with C₁₋₆alkyl (e.g., methyl), for            example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl,            1-methyl-pyrrolindin-2-yl-methyl or            1-methyl-pyrrolindin-3-yl-methyl);    -   2.18 Formula II or any of 2.5-2.10, wherein R₂ is -G-J wherein G        is a single bond and J is C₃₋₈cycloalkyl or heteroC₃₋₈cycloalkyl        (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein        the cycloalkyl and heterocycloalkyl group are optionally        substituted with one or more C₁₋₆alkyl or amino;    -   2.19 Formula II or any of 2.5-2.10, wherein R₂ is -G-J wherein G        is C₁₋₆alkylene (e.g., methylene) and J is C₃₋₈cycloalkyl or        heteroC₃₋₈cycloalkyl (e.g., oxetan-2-yl, pyrrolidin-3-yl,        pyrrolidin-2-yl) wherein the cycloalkyl and heterocycloalkyl        group are optionally substituted with one or more C₁₋₆alkyl or        amino;    -   2.20 Formula II or any of 2.5-2.10, wherein R₂ is        -   —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g., —C₀₋₄alkyl-cyclopentyl,            —C₀₋₄alkyl-cyclohexyl or —C₀₋₄alkyl-cyclopropyl), wherein            said cycloalkyl is optionally substituted with one or more            C₁₋₆alkyl or amino (for example, 2-aminocyclopentyl or            2-aminocyclohexyl),        -   —C₀₋₄alkyl-C₃₋₈heterocycloalkyl (e.g.,            —C₀₋₄alkyl-pyrrolidinyl, for example,            —C₀₋₄alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is            optionally substituted with C₁₋₆alkyl (e.g., methyl), for            example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl,            1-methyl-pyrrolindin-2-yl-methyl or            1-methyl-pyrrolindin-3-yl-methyl);    -   2.21 Formula II or any of 2.5-2.10, wherein R₂ is        2,2-dimethylpropyl;    -   2.22 Formula II or any of 2.5-2.10, wherein R₂ is isobutyl;    -   2.23 Formula II or any of 2.5-2.10, wherein R₂ is        1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl;    -   2.24 Formula II or any of 2.5-2.10, wherein R₂ is cyclopentyl;    -   2.25 Formula II or any of 2.5-2.10, wherein R₂ is        —C₀₋₄alkyl-pyrrolidinyl wherein the pyrrolidnyl is optionally        substituted with one or more C₁₋₆alkyl, e.g.,        1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl,        1-methyl-pyrrolindin-2-yl-methyl or        1-methyl-pyrrolindin-3-yl-methyl);    -   2.26 Formula II or any of 2.5-2.25, wherein R₃ is -D-E-F        wherein:        -   D is            -   a single bond,            -   C₁₋₆alkylene (e.g., methylene), or            -   arylC₁₋₆alkylene (e.g., benzylene or —CH₂C₆H₄—);        -   E is            -   a single bond,            -   C₁₋₄alkylene (e.g., methylene, ethynylene,                prop-2-yn-1-ylene),            -   C₀₋₄alkylarylene (e.g., phenylene or —C₆H₄—, -benzylene-                or —CH₂C₆H₄—), wherein the arylene group is optionally                substituted with halo (e.g., Cl or F),            -   heteroarylene (e.g., pyridinylene or pyrimidinylene),            -   aminoC₁₋₆alkylene (e.g., —CH₂N(H)—),            -   amino (e.g., —N(H)—);            -   C₃₋₈cycloalkylene optionally containing one or more                heteroatom selected from N, S or O (e.g.,                piperidinylene),        -   F is            -   H,            -   halo (e.g., F, Br, Cl),            -   C₁₋₆alkyl (e.g., isopropyl or isobutyl),            -   haloC₁₋₆alkyl (e.g., trifluoromethyl),            -   aryl (e.g., phenyl),            -   C₃₋₈cycloalkyl optionally containing one or more atom                selected from a group consisting of N, S or O (e.g.,                cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl,                tetrahydro-2H-pyran-4-yl, or morpholinyl), and                optionally substituted with one or more C₁₋₆alkyl (e.g.,                methyl or isopropyl), for example,                1-methylpyrrolidin-2-yl, pyrrolidin-1-yl,                pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,                1-ethylpiperidin-2-yl,            -   heteroaryl optionally substituted with one or more                C₁₋₆alkyl, halo (e.g., fluoro) or haloC₁₋₆alkyl (e.g.,                pyridyl (for example, pyrid-2-yl), pyrimidinyl (for                example, pyrimidin-2-yl), thiadiazolyl (for example,                1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for                example, pyrazol-1-yl) or imidazolyl (for example,                imidazol-1-yl, 4-methylimidazolyl,                1-methylimidazol-2-yl)), triazolyl (e.g.,                1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),                C₁₋₆alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol);            -   C₁₋₆alkoxy,            -   —O-haloC₁₋₆alkyl (e.g., —O—CF₃),            -   C₁₋₆alkylsulfonyl (for example, methylsulfonyl or                —S(O)₂CH₃),            -   —C(O)—R₁₃, wherein R₁₃ is —N(R₁₄)(R₁₅), C₁₋₆alkyl (e.g.,                methyl), —OC₁₋₆alkyl (e.g., —OCH₃), haloC₁₋₆alkyl                (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl,            -   —N(R₁₄)(R₁₅);    -   2.27 Formula 2.26, wherein R₁₃ is —N(R₁₄)(R₁₅), C₁₋₆alkyl (e.g.,        methyl), —OC₁₋₆alkyl (e.g., —OCH₃), haloC₁₋₆alkyl        (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl;    -   2.28 Formula 2.26, wherein D is C₁₋₆alkylene (e.g., methylene),        E is C₃₋₈cycloalkylene optionally containing one or more        heteroatom selected from N, S or O (e.g., piperidinylene) and F        is C₁₋₆alkyl (e.g., isopropyl or isobutyl), for example, R₃ is        isopropylpiperidin-1-ylmethyl;    -   2.29 Formula II or any of 2.5-2.25, wherein R₃ is a substituted        heteroarylC₀₋₆alkyl, e.g., substituted with haloC₁₋₆alkyl, for        example;    -   2.30 Formula II or any of 2.5-2.25, wherein R₃ is attached to        one of the nitrogens on the pyrazolo portion of Formula II and        is a moiety of Formula A

-   -   -   wherein:            -   X, Y and Z are, independently, N or C,            -   R₈, R₉, R₁₁ and R₁₂ are independently H or halogen                (e.g., Cl or F); and            -   R₁₀ is                -   halogen (e.g., fluoro or chloro),                -   C₁₋₆alkyl,                -   C₃₋₈cycloalkyl,                -   heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl or                    piperidinyl),                -   haloC₁₋₆alkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl,                    (for example, pyrid-2-yl) or e.g., thiadiazolyl (for                    example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g.,                    pyrazolyl (for example, pyrazol-1-yl) or imidazolyl                    (for example, imidazol-1-yl, 4-methylimidazolyl,                    1-methylimidazol-2-yl)), triazolyl (e.g.,                    1,2,4-triazol-1-yl), tetrazolyl (e.g.,                    tetrazol-5-yl), C₁₋₆alkyloxadiazolyl (e.g.,                    5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,                    pyrazol-1-yl),                -   wherein said aryl, heteroaryl, cycloalkyl or                    heterocycloalkyl is optionally substituted with one                    or more C₁₋₆alkyl (e.g., methyl), halogen (e.g.,                    chloro or fluoro), haloC₁₋₆alkyl (e.g.,                    trifluoromethyl), hydroxy, carboxy, —SH or an                    additional aryl or heteroaryl (e.g., biphenyl or                    pyridylphenyl)                -   C₁₋₆alkyl sulfonyl (e.g., methyl sulfonyl),                -   arylcarbonyl (e.g., benzoyl),                -   heteroarylcarbonyl,                -   C₁₋₆alkoxycarbonyl, (e.g., methoxycarbonyl),                -   aminocarbonyl                -   —N(R₁₄)(R₁₅);            -   preferably R₁₀ is phenyl or pyridyl, e.g., 2-pyridyl,                optionally substituted with one or more C₁₋₆alkyl (e.g.,                methyl), halogen (e.g., chloro or fluoro), haloC₁₋₆alkyl                (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an                additional aryl or heteroaryl (e.g., biphenyl or                pyridylphenyl);            -   provided that when X, Y or Z is nitrogen, R₈, R₉ or R₁₀,                respectively, is not present;

    -   2.31 Formula 2.30, wherein X, Y and/or Z are independently        nitrogen and R₈, R₉, R₁₁ and R₁₂ are H provided that when X, Y        or Z are nitrogen, R₈, R₉ and R₁₀, respectively, are not        present;

    -   2.32 Formula 2.30, wherein R₃ is X, Y and Z are C and R₈, R₉,        R₁₁ and R₁₂ are H,

    -   2.33 Formulae 2.30, 2.31 or 2.32, wherein R₁₀ is        -   halogen (e.g., fluoro or chloro),        -   C₁₋₆alkyl,        -   C₃₋₈cycloalkyl,        -   heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl or piperidinyl),        -   haloC₁₋₆alkyl (e.g., trifluoromethyl),        -   aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl, (for            example, pyrid-2-yl) or e.g., thiadiazolyl (for example,            1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for            example, pyrazol-1-yl) or imidazolyl (for example,            imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl),            tetrazolyl (e.g., tetrazol-5-yl), C₁₋₆alkyloxadiazolyl            (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,            pyrazol-1-yl),        -   wherein said aryl, heteroaryl, cycloalkyl or            heterocycloalkyl is optionally substituted with one or more            C₁₋₆alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),            haloC₁₋₆alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH            or an additional aryl or heteroaryl (e.g., biphenyl or            pyridylphenyl),        -   C₁₋₆alkyl sulfonyl (e.g., methyl sulfonyl),        -   arylcarbonyl (e.g., benzoyl),        -   heteroarylcarbonyl,        -   C₁₋₆alkoxycarbonyl, (e.g., methoxycarbonyl),        -   aminocarbonyl,        -   —N(R₁₄)(R₁₅);

    -   2.34 Any of formulae 2.30-2.33, wherein R₁₀ is halogen (e.g.,        fluoro or chloro);

    -   2.35 Any of formulae 2.30-2.33, wherein R₁₀ is haloC₁₋₆alkyl        (e.g., trifluoromethyl);

    -   2.36 Any of formulae 2.30-2.33, wherein R₁₀ is C₃₋₈cycloalkyl;

    -   2.37 Any of formulae 2.30-2.33, wherein R₁₀ is C₁₋₆alkyl        sulfonyl (e.g., methyl sulfonyl);

    -   2.38 Any of formulae 2.30-2.33, wherein R₁₀ is arylcarbonyl        (e.g., benzoyl);

    -   2.39 Any of formulae 2.30-2.33, wherein R₁₀ is        heteroarylcarbonyl;

    -   2.40 Any of formulae 2.30-2.33, wherein R₁₀ is        C₁₋₆alkoxycarbonyl, (e.g., methoxycarbonyl);

    -   2.41 Any of formulae 2.30-2.33, wherein R₁₀ is aminocarbonyl;

    -   2.42 Any of formulae 2.30-2.33, wherein R₁₀ is aryl (e.g.,        phenyl), wherein said aryl is optionally substituted with one or        more C₁₋₆alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),        haloC₁₋₆alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or        an additional aryl or heteroaryl (e.g., biphenyl);

    -   2.43 Any of formulae 2.30-2.33, wherein R₁₀ is heteroaryl (e.g.,        pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for        example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for        example, pyrazol-1-yl) or imidazolyl (for example,        imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl        (e.g., tetrazol-5-yl), C₁₋₆alkyloxadiazolyl (e.g.,        5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl),        wherein said heteroaryl is optionally substituted with one or        more C₁₋₆alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),        haloC₁₋₆alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or        an additional aryl or heteroaryl (e.g., biphenyl or        pyridylphenyl);

    -   2.44 Any of formulae 2.30-2.34, wherein R₁₀ is triazolyl (e.g.,        1,2,4-triazol-1-yl);

    -   2.45 Any of formulae 2.30-2.34, wherein R₁₀ is pyridyl (e.g.,        pyrid-2-yl) optionally substituted with one or more C₁₋₆alkyl        (e.g., methyl), halogen (e.g., chloro or fluoro);

    -   2.46 Any of formulae 2.30-2.34, wherein R₁₀ is pyridyl (e.g.,        pyrid-2-yl);

    -   2.47 Any of formulae 2.30-2.34, wherein R₁₀ is 6-fluoro-pyridyl        (e.g., 6-fluoro-pyrid-2-yl);

    -   2.48 Any of formulae 2.30-2.33, wherein R₁₀ is —N(R₁₄)(R₁₅);

    -   2.49 Formula II or any of 2.1-2.48, wherein R₄ is:        -   C₁₋₆alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl),        -   C₃₋₈cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   C₃₋₈heterocycloalkyl (e.g., pyrrolidinyl (for example            pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for            example, piperidin-1-yl), morpholinyl),        -   —C₀₋₆alkylaryl (e.g., phenyl or benzyl) or            —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or            pyrazol-3-yl) wherein said aryl or heteroaryl is optionally            substituted with one or more halo (e.g., 4-fluorophenyl),            hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or            another aryl group (e.g., biphenyl-4-ylmethyl);

    -   2.50 Formula II or any of 2.1-2.49, wherein R₄ is:        -   C₃₋₈cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   C₃₋₈heterocycloalkyl (e.g., pyrrolidinyl (for example            pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for            example, piperidin-1-yl), morpholinyl),        -   —C₀₋₆alkylaryl (e.g., phenyl or benzyl) or            —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or            pyrazol-3-yl) wherein said aryl or heteroaryl is optionally            substituted with one or more halo (e.g., 4-fluorophenyl),            hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or            another aryl group (e.g., biphenyl-4-ylmethyl).

    -   2.51 Formula 2.50, wherein R₄ is C₁₋₆alkyl (e.g., methyl,        isopropyl, isobutyl, n-propyl);

    -   2.52 Formula 2.50, wherein R₄ is C₃₋₈cycloalkyl (e.g.,        cyclopentyl or cyclohexyl);

    -   2.53 Formula 2.50, wherein R₄ is C₃₋₈heterocycloalkyl (e.g.,        pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl),        piperidinyl (for example, piperidin-1-yl), morpholinyl);

    -   2.54 Formula 2.50, wherein R₄ is —C₀₋₆alkylaryl (e.g., phenyl or        benzyl) or —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or        pyrazol-3-yl) wherein said aryl or heteroaryl is optionally        substituted with one or more halo (e.g., 4-fluorophenyl),        hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or        another aryl group (e.g., biphenyl-4-ylmethyl);

    -   2.55 Formula 2.50, wherein R₄ is phenyl optionally substituted        with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g.,        4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or another aryl group        (e.g., biphenyl-4-ylmethyl);

    -   2.56 Formula 2.50, wherein R₄ is phenyl;

    -   2.57 Formula 2.50, wherein R₄ is 4-fluorophenyl;

    -   2.58 Formula 2.50, wherein R₄ is 4-hydroxyphenyl;

    -   2.59 Formula 2.50, wherein R₄ is C₃₋₈cycloalkyl (e.g.,        cyclopentyl or cyclohexyl),

    -   2.60 Any of the preceding formulae wherein R₆ is H, C₁₋₆alkyl        (e.g., methyl or ethyl) or C₃₋₈cycloalkyl;

    -   2.61 Any of the preceding formulae wherein R₆ is C₃₋₈cycloalkyl;

    -   2.62 Any of the preceding formulae wherein R₆ is H,

    -   2.63 Any of the preceding formulae wherein R₆ is C₁₋₆alkyl        (e.g., methyl or ethyl);

    -   2.64 Any of the preceding formulae wherein R₁₄ and R₁₅ are        independently H or C₁₋₆alkyl;

    -   2.65 Any of the preceding formulae wherein R₁₄ and R₁₅ are H,

    -   2.66 Any of the preceding formulae wherein the Compound is        selected from:

-   -   2.67 any of the preceding formulae wherein the compounds inhibit        phosphodiesterase-mediated (e.g., PDE1-mediated, especially        PDE1B-mediated) hydrolysis of cGMP, e.g., with an IC₅₀ of less        than 1 μM, preferably less than 25 nM, preferably less than 10        nM in an immobilized-metal affinity particle reagent PDE assay,        for example, as described in Example 5;

In another aspect, the Compound of Formula II is a Compound of FormulaII(a):

wherein

-   -   (i) Q is —C(═O)—, —C(═S)—, —C(═N(R₆))— or —C(R₁₄)(R₁₅)—;    -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);    -   (iii) R₂ is C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl        or 2,2-dimethylpropyl) wherein said alkyl group is optionally        substituted with one or more halo (e.g., fluoro) or hydroxy        (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or        3-hydroxy-2-methylpropyl),    -   (iv) R₃ is attached to one of the nitrogens on the pyrazolo        portion of Formula II(a) and is a moiety of Formula A

-   -   -   wherein:            -   X, Y and Z are, independently, N or C,            -   R₈, R₉, R₁₁ and R₁₂ are independently H or halogen                (e.g., Cl or F); and            -   R₁₀ is                -   halogen (e.g., fluoro or chloro),                -   C₁₋₆alkyl,                -   C₃₋₈cycloalkyl,                -   heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl or                    piperidinyl),                -   haloC₁₋₆alkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl,                    (for example, pyrid-2-yl) or e.g., thiadiazolyl (for                    example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g.,                    pyrazolyl (for example, pyrazol-1-yl) or imidazolyl                    (for example, imidazol-1-yl)), triazolyl (e.g.,                    1,2,4-triazol-1-yl), tetrazolyl (e.g.,                    tetrazol-5-yl), C₁₋₆alkyloxadiazolyl (e.g.,                    5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,                    pyrazol-1-yl),                -   wherein said aryl, heteroaryl, cycloalkyl or                    heterocycloalkyl is optionally substituted with one                    or more C₁₋₆alkyl (e.g., methyl), halogen (e.g.,                    chloro or fluoro), haloC₁₋₆alkyl (e.g.,                    trifluoromethyl), hydroxy, carboxy, —SH or an                    additional aryl or heteroaryl (e.g., biphenyl or                    pyridylphenyl)                -   C₁₋₆alkyl sulfonyl (e.g., methyl sulfonyl),                -   arylcarbonyl (e.g., benzoyl),                -   heteroarylcarbonyl,                -   C₁₋₆alkoxycarbonyl, (e.g., methoxycarbonyl),                -   Aminocarbonyl,                -   —N(R₁₄)(R₁₅);                -   preferably R₁₀ is phenyl or pyridyl, e.g.,                    2-pyridyl, optionally substituted with one or more                    C₁₋₆alkyl (e.g., methyl), halogen (e.g., chloro or                    fluoro), haloC₁₋₆alkyl (e.g., trifluoromethyl),                    hydroxy, carboxy, —SH or an additional aryl or                    heteroaryl (e.g., biphenyl or pyridylphenyl);                -   provided that when X, Y or Z is nitrogen, R₈, R₉ or                    R₁₀, respectively, is not present;

    -   (v) R₄ is:        -   C₁₋₆alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl),        -   C₃₋₈cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   C₃₋₈heterocycloalkyl (e.g., pyrrolidinyl (for example            pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for            example, piperidin-1-yl), morpholinyl),        -   —C₀₋₆alkylaryl (e.g., phenyl or benzyl) or            —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or            pyrazol-3-yl) wherein said aryl or heteroaryl is optionally            substituted with one or more halo (e.g., 4-fluorophenyl),            hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or            another aryl group (e.g., biphenyl-4-ylmethyl);

    -   (vi) R₆ is H, C₁₋₆alkyl (e.g., methyl or ethyl) or        C₃₋₈cycloalkyl;

    -   (vii) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl,        in free or salt form.

In another aspect, the Compound of Formula II is a compound of FormulaII(b):

wherein:

-   -   (i) Q is —C(═O)—, —C(═S)—, —C(═N(R₆))— or —C(R₁₄)(R₁₅)—;    -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);    -   (iii) R₂ is C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl        or 2,2-dimethylpropyl) wherein said alkyl group is optionally        substituted with one or more halo (e.g., fluoro) or hydroxy        (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or        3-hydroxy-2-methylpropyl),    -   (iv) R₃ is attached to one of the nitrogens on the pyrazolo        portion of Formula II(b) and is a moiety of Formula A

-   -   -   wherein:            -   X, Y and Z are, independently, N or C,            -   R₈, R₉, R₁₁ and R₁₂ are independently H or halogen                (e.g., Cl or F); and            -   R₁₀ is phenyl or pyridyl, e.g., 2-pyridyl, or                pyrrolidinyl optionally substituted with one or more                C₁₋₆alkyl (e.g., methyl), halogen (e.g., chloro or                fluoro), haloC₁₋₆alkyl (e.g., trifluoromethyl), hydroxy,                carboxy, —SH or an additional aryl or heteroaryl (e.g.,                biphenyl or pyridylphenyl);            -   provided that when X, Y or Z is nitrogen, R₈, R₉ or R₁₀,                respectively, is not present;

    -   (v) R₄ is:        -   C₁₋₆alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl),        -   C₃₋₈cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   C₃₋₈heterocycloalkyl (e.g., pyrrolidinyl (for example            pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for            example, piperidin-1-yl), morpholinyl),        -   —C₀₋₆alkylaryl (e.g., phenyl or benzyl) or            —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or            pyrazol-3-yl) wherein said aryl or heteroaryl is optionally            substituted with one or more halo (e.g., 4-fluorophenyl),            hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or            another aryl group (e.g., biphenyl-4-ylmethyl);

    -   (vi) R₆ is H, C₁₋₆alkyl (e.g., methyl or ethyl) or        C₃₋₈cycloalkyl;

    -   (vii) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl,        in free or salt form.

In another aspect, the Compound of Formula II is a compound of FormulaII(c):

wherein:

-   -   (i) Q is —C(═O)—, —C(═S)—, —C(═N(R₆))— or —C(R₁₄)(R₅)—;    -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);    -   (iii) R₂ is C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl        or 2,2-dimethylpropyl) wherein said alkyl group is optionally        substituted with one or more halo (e.g., fluoro) or hydroxy        (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or        3-hydroxy-2-methylpropyl),    -   (iv) R₃ is attached to one of the nitrogens on the pyrazolo        portion of Formula II(c) and is a moiety of Formula A

-   -   -   wherein:            -   X, Y and Z are, independently, N or C,            -   R₈, R₉, R₁₁ and R₁₂ are independently H or halogen                (e.g., Cl or F); and            -   R₁₀ is phenyl or pyridyl, e.g., 2-pyridyl, pyrrolidinyl                optionally substituted with one or more C₁₋₆alkyl (e.g.,                methyl), halogen (e.g., chloro or fluoro), haloC₁₋₆alkyl                (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an                additional aryl or heteroaryl (e.g., biphenyl or                pyridylphenyl);            -   provided that when X, Y or Z is nitrogen, R₈, R₉ or R₁₀,                respectively, is not present;

    -   (v) R₄ is:        -   —C₀₋₆alkylaryl (e.g., phenyl or benzyl) or            —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or            pyrazol-3-yl) wherein said aryl or heteroaryl is optionally            substituted with one or more halo (e.g., 4-fluorophenyl),            hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or            another aryl group (e.g., biphenyl-4-ylmethyl);

    -   (vi) R₆ is H or C₁₋₆alkyl (e.g., methyl or ethyl);

    -   (vii) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl,        in free or salt form.

In another aspect, the Compound of Formula II is a Compound of FormulaII(d):

wherein:

-   -   (i) Q is —C(═O)—, —C(═S)—, —C(═N(R₆))— or —C(R₁₄)(R₁₅)—;    -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);    -   (iii) R₂ is C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl        or 2,2-dimethylpropyl) wherein said alkyl group is optionally        substituted with one or more halo (e.g., fluoro) or hydroxy        (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or        3-hydroxy-2-methylpropyl),    -   (iv) R₃ is attached to one of the nitrogens on the pyrazolo        portion of Formula II(d) and is a moiety of Formula A

-   -   -   wherein:            -   X, Y and Z are, independently, N or C,            -   R₈, R₉, R₁₁ and R₁₂ are independently H or halogen                (e.g., Cl or F); and            -   R₁₀ is phenyl or pyridyl, e.g., 2-pyridyl, pyrrolidinyl                optionally substituted with one or more C₁₋₆alkyl (e.g.,                methyl), halogen (e.g., chloro or fluoro), haloC₁₋₆alkyl                (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an                additional aryl or heteroaryl (e.g., biphenyl or                pyridylphenyl);            -   provided that when X, Y or Z is nitrogen, R₈, R₉ or R₁₀,                respectively, is not present;

    -   (v) R₄ is:        -   C₃₋₈cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   C₃₋₈heterocycloalkyl (e.g., pyrrolidinyl (for example            pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for            example, piperidin-1-yl), morpholinyl),        -   —C₀₋₆alkylaryl (e.g., phenyl or benzyl) or            —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or            pyrazol-3-yl) wherein said aryl or heteroaryl is optionally            substituted with one or more halo (e.g., 4-fluorophenyl),            hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or            another aryl group (e.g., biphenyl-4-ylmethyl);

    -   (vi) R₆ is H, C₁₋₆alkyl (e.g., methyl or ethyl);

    -   (vii) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl,        in free or salt form.

In another aspect, the Compound of Formula II is a Compound of FormulaII(e):

wherein:

-   -   (i) Q is —C(═O)—, —C(═S)—, —C(═N(R₆))— or —C(R₁₄)(R₁₅)—;    -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);    -   (iii) R₂ is C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl        or 2,2-dimethylpropyl) wherein said alkyl group is optionally        substituted with one or more halo (e.g., fluoro) or hydroxy        (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or        3-hydroxy-2-methylpropyl),    -   (iv) R₃ is attached to one of the nitrogens on the pyrazolo        portion of Formula II(e) and is a moiety of Formula A

-   -   -   wherein:            -   X, Y and Z are, independently, N or C,            -   R₈, R₉, R₁₁ and R₁₂ are independently H or halogen                (e.g., Cl or F); and            -   R₁₀ is phenyl, pyridyl (e.g., 2-pyridyl), pyrrolidinyl                (e.g., pyrrolidin-3-yl or pyrrolidin-1-yl) or                piperidinyl (e.g., piperidin-1-yl), optionally                substituted with one or more C₁₋₆alkyl (e.g., methyl) or                halogen (e.g., chloro or fluoro);            -   provided that when X, Y or Z is nitrogen, R₈, R₉ or R₁₀,                respectively, is not present;

    -   (v) R₄ is phenyl optionally substituted with one or more halo        (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl),        C₁₋₆alkyl, C₁₋₆alkoxy or another aryl group (e.g.,        biphenyl-4-ylmethyl);

    -   (vi) R₆ is H or C₁₋₆alkyl (e.g., methyl or ethyl);

    -   (vii) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl, in free or        salt form.

In still another aspect, the Compound of Formula II is a Compound ofFormula II(f):

wherein:

-   -   (i) Q is —C(═O)—;    -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);    -   (iii) R₂ is C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl        or 2,2-dimethylpropyl);    -   (iv) R₃ is attached to one of the nitrogens on the pyrazolo        portion of Formula II(f) and is a moiety of Formula A

-   -   -   wherein:            -   X, Y and Z are C;            -   R₈, R₉, R₁₁ and R₁₂ are H; and            -   R₁₀ is pyridyl (e.g., 2-pyridyl), optionally substituted                with one or more halogen (e.g., fluoro);

    -   (v) R₄ is        -   phenyl optionally substituted with one or more halo (e.g.,            4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl,            C₁₋₆alkoxy or another aryl group (e.g.,            biphenyl-4-ylmethyl), preferably phenyl;        -   C₁₋₆alkyl (e.g., n-propyl),        -   C₃₋₈cycloalkyl (e.g., cyclopentyl),            in free or salt form.

In still another embodiment, the compound of the invention ashereinbefore described is selected from any of the following:

in free or salt form.

Preferably, the compound of Formula II or any of II(a)-II(e) is acompound wherein Q is —C(═O)—.

In a particular embodiment, the Compound of any of Formulae II,II(a)-II(f), 2.1-2.67 contains the proviso that said compound is not:

-   (a)    7-[(2,4-dichlorophenyl)methyl]-3-ethoxy-2,5-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;-   (b)    7-[(4-chlorophenyl)methyl]-3-ethoxy-2,5-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;-   (c)    2-[(2,5-dichlorophenyl)methyl]-3-ethoxy-5,7-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;-   (d)    2-[(4-bromophenyl)methyl]-3-ethoxy-5,7-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;-   (e)    3-[(4-methoxyphenyl)methoxy]-2,5,7-trimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;-   (f)    1-[(3-bromophenyl)methyl]-5,7-dimethyl-3-(2-propen-1-yloxy)-1H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione.

If not otherwise specified or clear from context, the following termsherein have the following meanings:

-   -   (a) “Alkyl” as used herein is a saturated or unsaturated        hydrocarbon moiety, preferably saturated, preferably having one        to six carbon atoms, which may be linear or branched, and may be        optionally mono-, di- or tri-substituted, e.g., with halogen        (e.g., chloro or fluoro), hydroxy, or carboxy.    -   (b) “Cycloalkyl” as used herein is a saturated or unsaturated        nonaromatic hydrocarbon moiety, preferably saturated, preferably        comprising three to eight carbon atoms, at least some of which        form a nonaromatic mono- or bicyclic, or bridged cyclic        structure, and which may be optionally substituted, e.g., with        halogen (e.g., chloro or fluoro), hydroxy, or carboxy. Wherein        the cycloalkyl optionally contains one or more atoms selected        from N and O and/or S, said cycloalkyl may optionally be a        heterocycloalkyl.    -   (c) “Heterocycloalkyl” is, unless otherwise indicated, saturated        or unsaturated nonaromatic hydrocarbon moiety, preferably        saturated, preferably comprising three to nine carbon atoms, at        least some of which form a nonaromatic mono- or bicyclic, or        bridged cyclic structure, wherein at least one carbon atom is        replaced with N, O or S, which heterocycloalkyl may be        optionally substituted, e.g., with halogen (e.g., chloro or        fluoro), hydroxy, or carboxy.    -   (d) “Aryl” as used herein is a mono or bicyclic aromatic        hydrocarbon, preferably phenyl, optionally substituted, e.g.,        with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),        haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an        additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl).    -   (e) “Heteroaryl” as used herein is an aromatic moiety wherein        one or more of the atoms making up the aromatic ring is sulfur        or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl,        which may be optionally substituted, e.g., with alkyl, halogen,        haloalkyl, hydroxy or carboxy.    -   (f) Wherein E is phenylene, the numbering is as follows:

-   -   (g) It is intended that wherein the substituents end in “ene”,        for example, alkylene, phenylene or arylalkylene, said        substitutents are intended to bridge or be connected to two        other substituents. Therefore, methylene is intended to be —CH₂—        and phenylene intended to be —C₆H₄— and arylalkylene is intended        to be —C₆H₄—CH₂— or —CH₂—C₆H₄—.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.Similarly, the substituents defined for the Compounds of the Inventionare intended to result in stable compounds.

Compounds of the Invention may exist in free or salt form, e.g., as acidaddition salts. In this specification unless otherwise indicated,language such as “Compounds of the Invention” is to be understood asembracing the compounds described herein, e.g., (1- or 2- and/or 5and/or 7-substituted)-(3-oxy)-(4H,4-imino, 4-thioxo or4-oxo)-pyrazolo[3,4-d]pyrimidin-6-ones, e.g., a compound of formula II,or any of II(a)-II(f), or 2.1-2.67, in any form, for example free oracid addition salt form, or where the compounds contain acidicsubstituents, in base addition salt form. The Compounds of the Inventionare intended for use as pharmaceuticals, therefore pharmaceuticallyacceptable salts are preferred. Salts which are unsuitable forpharmaceutical uses may be useful, for example, for the isolation orpurification of free Compounds of the Invention or theirpharmaceutically acceptable salts, are therefore also included. In aparticular embodiment, the salt of the compounds of the invention is aformic acid addition salt.

Compounds of the Invention may in some cases also exist in prodrug form.A prodrug form is compound which converts in the body to a Compound ofthe Invention. For example, when the Compounds of the Invention containhydroxy (or carboxy) substituents, these substituents may formphysiologically hydrolysable and acceptable esters, e.g., C₁₋₄alkylcarboxylic acid ester. As used herein, “physiologically hydrolysable andacceptable ester” means esters of Compounds of the Invention which arehydrolysable under physiological conditions to yield acids (in the caseof Compounds of the Invention which have hydroxy substituents) oralcohols (in the case of Compounds of the Invention which have carboxysubstituents) which are themselves physiologically tolerable at doses tobe administered. Therefore, wherein the Compound of the Inventioncontains a hydroxy group, for example, Compound-OH, the acyl esterprodrug of such compound, i.e., Compound-O—C(O)—C₁₋₄alkyl, can hydrolyzein the body to form physiologically hydrolysable alcohol (Compound-OH)on the one hand and acid on the other (e.g., HOC(O)—C₁₋₄alkyl).Alternatively, wherein the Compound of the Invention contains acarboxylic acid, for example, Compound-C(O)OH, the acid ester prodrug ofsuch compound, Compound-C(O)O—C₁₋₄alkyl can hydrolyze to formCompound-C(O)OH and HO—C₁₋₄alkyl. As will be appreciated, the term thusembraces conventional pharmaceutical prodrug forms.

The invention also provides methods of making the Compounds of theInvention and methods of using the Compounds of the Invention fortreatment of diseases and disorders as set forth below (especiallytreatment of diseases characterized by reduced dopamine D1 receptorsignaling activity, such as Parkinson's disease, Tourette's Syndrome,Autism, fragile X syndrome, ADHD, restless leg syndrome, depression,cognitive impairment of schizophrenia, narcolepsy and diseases that maybe alleviated by the enhancement of progesterone-signaling such asfemale sexual dysfunction), or a disease or disorder such as psychosisor glaucoma). This list is not intended to be exhaustive and may includeother diseases and disorders as set forth below.

In another embodiment, the invention further provides a pharmaceuticalcomposition comprising a Compound of the Invention, e.g., (1- or 2-and/or 5 and/or 7-substituted)-(3-oxy)-(4H,4-imino, 4-thioxo or4-oxo)-pyrazolo[3,4-d]pyrimidin-6-ones, e.g., a compound of formula II,or any of II(a)-II(f), or 2.1-2.67, in free or pharmaceuticallyacceptable salt form, in admixture with a pharmaceutically acceptablecarrier.

DETAILED DESCRIPTION OF THE INVENTION

Methods of Making Compounds of the Invention

The Compounds of the Invention and their pharmaceutically acceptablesalts may be made using the methods as described and exemplified hereinand by methods similar thereto and by methods known in the chemical art.Such methods include, but not limited to, those described below. In thedescription of the synthetic methods described herein, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Therefore, at times, the reaction may require to berun at elevated temperature or for a longer or shorter period of time.It is understood by one skilled in the art of organic synthesis thatfunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. If not commerciallyavailable, starting materials for these processes may be made byprocedures, which are selected from the chemical art using techniqueswhich are similar or analogous to the synthesis of known compounds. Inparticular, the intermediates and starting materials for the Compoundsof the Invention may be prepared by methods and processes as describedin WO 2007/143705; WO 2009/073210; PCT/US2009/06444; andPCT/US2009/06443. All references cited herein are hereby incorporated byreference in their entirety.

The Compounds of the Invention include their enantiomers,diastereoisomers and racemates, as well as their polymorphs, hydrates,solvates and complexes. Some individual compounds within the scope ofthis invention may contain double bonds. Representations of double bondsin this invention are meant to include both the E and the Z isomer ofthe double bond. In addition, some compounds within the scope of thisinvention may contain one or more asymmetric centers. This inventionincludes the use of any of the optically pure stereoisomers as well asany combination of stereoisomers.

As will be appreciated by those skilled in the art, the Compounds of theInvention may exhibit keto-enol tautomerization. Therefore, theinvention as defined in the present invention is to be understood asembracing both the structures as setforth herewith and their tautomericforms.

It is also intended that the Compounds of the Invention encompass theirstable and unstable isotopes. Stable isotopes are nonradioactiveisotopes which contain one additional neutron compared to the abundantnuclides of the same species (i.e., element). It is expected that theactivity of compounds comprising such isotopes would be retained, andsuch compound would also have utility for measuring pharmacokinetics ofthe non-isotopic analogs. For example, the hydrogen atom at a certainposition on the Compounds of the Invention may be replaced withdeuterium (a stable isotope which is non-raradioactive). Examples ofknown stable isotopes include, but not limited to, deuterium, ¹³C, ¹⁵N,¹⁸O. Alternatively, unstable isotopes, which are radioactive isotopeswhich contain additional neutrons compared to the abundant nuclides ofthe same species (i.e., element), e.g., ¹²³I, ¹³¹I, ¹²⁵I, ¹¹C, ¹⁸F, mayreplace the corresponding abundant species, e.g., I, C and Frespectively. Another example of useful isotope of the compound of theinvention is the ¹¹C isotope. These radio isotopes are useful forradio-imaging and/or pharmacokinetic studies of the compounds of theinvention. Methods of making isotopes of PDE1 inhibitors disclosed in WO2011/043816, the contents of which are incorporated by reference intheir entirety, may be used for making the isotopes of the compounds ofthe current invention.

Melting points are uncorrected and (dec) indicates decomposition.Temperature are given in degrees Celsius (° C.); unless otherwisestated, operations are carried out at room or ambient temperature, thatis, at a temperature in the range of 18-25° C. Chromatography meansflash chromatography on silica gel; thin layer chromatography (TLC) iscarried out on silica gel plates. NMR data is in the delta values ofmajor diagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard. Conventionalabbreviations for signal shape are used. Coupling constants (J) aregiven in Hz. For mass spectra (MS), the lowest mass major ion isreported for molecules where isotope splitting results in multiple massspectral peaks Solvent mixture compositions are given as volumepercentages or volume ratios. In cases where the NMR spectra arecomplex, only diagnostic signals are reported.

Terms and abbreviations:

-   -   BOC=di-tert-butyl dicarbonate,    -   BuLi=n-butyllithium    -   Bu^(t)OH=tert-butyl alcohol,    -   CAN=ammonium cerium (IV) nitrate,    -   DIPEA=diisopropylethylamine,    -   DMF=N,N-dimethylforamide,    -   DMSO=dimethyl sulfoxide,    -   Et₂O=diethyl ether,    -   EtOAc=ethyl acetate,    -   equiv.=equivalent(s),    -   h=hour(s),    -   HPLC=high performance liquid chromatography,    -   K₂CO₃=potassium carbonate,    -   LDA=lithium diisopropylamide    -   MeOH=methanol,    -   NaHCO₃=sodium bicarbonate,    -   NBS=N-bromosuccinimide    -   NCS=N-chlorosuccinimide    -   NH₄OH=ammonium hydroxide,    -   Pd₂(dba)₃=tris[dibenzylideneacetone]dipalladium(0)    -   PMB=p-methoxybenzyl,    -   POCl₃=phosphorous oxychloride,    -   SOCl₂=thionyl chloride,    -   TFA=trifluoroacetic acid,    -   THF=tetrahedrofuran.

The synthetic methods in this invention are illustrated below. Thesignificances for the R groups are as set forth in any of the formulaeabove, e.g., for formula II, II(a)-II(f) unless otherwise indicated.

In an aspect of the invention, intermediate compounds of formula IIb canbe synthesized by reacting a compound of formula IIa with a dicarboxylicacid, acetic anhydride and acetic acid mixing with heat, e.g., to about90° C. for about 3 hours and then cooled.

wherein R₁ is H or C₁₋₄alkyl [e.g., methyl].

Intermediate IIc can be prepared by for example reacting intermediate ofIIb with for example a chlorinating compound such as POCl₃, sometimeswith small amounts of water and heated, e.g., heating to about 80° C.for about 4 hours and then cooled.

Intermediate IId may be formed by reacting intermediate IIc with forexample a P¹-L in a solvent such as DMF and a base such as K₂CO₃, sodiumbicarbonate, cesium carbonate, sodium hydroxide, triethylamine,diisopropylethylamine or the like at room temperature or with heating.

wherein P¹ is a protective group [e.g., p-methoxybenzyl group (PMB) orBOC]; L is a leaving group such as a halogen, mesylate, or tosylate.Preferably, P¹ is PMB and the base is potassium carbonate.

Intermediate IIe may be prepared by reacting intermediate IId withhydrazine or hydrazine hydrate in a solvent such as methanol and withheating, e.g. refluxed for about 4 hours and then cooled.

Intermediate IIf can be synthesized by for example reacting intermediateIIe with POCl₃ and DMF (Reaction 1):

Intermediate IIg may be formed by reacting intermediate IIf with forexample a R₃-L in a solvent such as DMF and a base such as K₂CO₃, sodiumbicarbonate, cesium carbonate, triethylamine or the like, preferablyK₂CO₃, at room temperature or with heating (Reaction 2):

wherein R₃ is as defined previously [e.g. -D-E-F or moiety of FormulaA]; L is a leaving group such as a halogen, mesylate, or tosylate.

Intermediate IIh may be formed by reacting intermediate IIg with forexample C₂Cl₆, NCS, NBS or I₂ in a solvent such as THF and a base suchas LiHMDS, LDA or BuLi at low temperature (Reaction 3):

Intermediate IIi (Compound of the Invention with R₂═P¹) may be formed byreacting intermediate IIh with for example a R₄OH in a solvent such asDMF and a base such as K₂CO₃ with heating. Sometimes, R₄OH itself can beused as a solvent (Reaction 4):

wherein R₄ is as defined previously in any of Formulae II orII(a)-II(f).

Intermediate IIj (i.e., Compound of the Invention wherein R₂═H) may besynthesized from intermediate IIi by removing the protective group P¹with an appropriate method. For example, if P¹ is a p-methoxybenzylgroup, it can be removed by for example TFA/TFMSA in methylene chlorideat room temperature (Reaction 5):

Wherein P¹ is BOC, the compound may be deprotected by using acid such ashydrochloric acid or TFA.

The Compounds of the Invention may be formed by reacting intermediateIIj with for example a R₂-L in a solvent such as DMF and a base such asK₂CO₃ at room temperature or with heating (Reaction 6):

wherein L is a leaving group such as a halogen, mesylate, or tosylate.

Alternatively, the Compounds of the Invention may be prepared in theorder as described below.

Intermediate IIIa may be formed by reacting intermediate IIc with forexample a R₂-L in a solvent such as DMF and a base such as K₂CO₃ at roomtemperature or with heating (Reaction 7).

Intermediate IIIb may be prepared by reacting intermediate IIIa withanhydrous hydrazine or hydrazine hydrate in a solvent such as methanoland heated for several hours and then cooled (Reaction 8):

Intermediate IIIc may be formed by for example reacting intermediateIIIb with POCl₃ and DMF (Reaction 10):

Intermediate IIId may be formed by reacting intermediate IIIc with forexample a R₃-L in a solvent such as DMF and a base such as K₂CO₃, sodiumbicarbonate, cesium carbonate, triethylamine or the like, preferablyK₂CO₃, at room temperature or with heating (Reaction 11):

Intermediate IIIe may be formed by reacting intermediate IIId with forexample C₂Cl₆, NCS, NBS or I₂ in a solvent such as THF and a base suchas LiHMDS, LDA or BuLi at low temperature (Reaction 12):

Compound of Formula II may be formed by reacting intermediate IIIe withfor example a R₄OH in a solvent such as DMF and a base such as K₂CO₃with heating. Sometimes, R₄OH itself can be used as a solvent (Reaction13):

The 4-thioxo Compounds of the Invention, i.e., any of Formulae II orII(a)-II(f), wherein Q is C(═S) may then be prepared by reacting thedione Compounds of the Invention, i.e., any of Formulae II orII(a)-II(f), wherein Q is C(═O) with P₄S₁₀ in a microwave vial in thepresence of a base, e.g., pyridine, and heating the mixture to anelevated temperature, e.g., in a microwave, e.g., to about 150° C.

The 4-imino Compounds of the Invention, i.e., any of Formulae II orII(a)-II(f), wherein Q is C(═N(R₆)) may in turn be converted from thethioxo compound (I.e., any of Formulae II or II(a)-II(f), wherein with Qis X(═S)) by reacting the 4-thioxo compound with NH₂(R₆) in the presenceof HgCl₂, e.g., in a solvent such as THF, and heating the reactionmixture to an elevated temperature, e.g., in a microwave, e.g., to about110° C.

The Compounds of the Invention, any of Formulae II or II(a)-II(f),wherein Q is C(R₁₄)(R₁₅) may also be prepared by reacting the dioneCompounds of the Invention, i.e., any of Formulae II or II(a)-II(f),wherein Q is C(═O) with a reducing agent, e.g., diisobutylaluminumhydride (DIBAL-H), lithium aluminum hydride, sodium borohydride,preferably, DIBAL-H.

The invention thus provides methods of making a 4-thioxo Compounds ofthe Invention, i.e., any of Formulae II or II(a)-II(f), wherein Q isC(═S) as hereinbefore described, for example, comprising reacting aCompound of Formula II wherein Q is C(═O), with P₄S₁₀ in the presence ofa base, e.g., pyridine, and heating the reaction mixture to an elevatedtemperature, e.g., to >50° C., e.g., >100° C., e.g., >150° C., forexample, in a microwave to about 150° C.

The invention also provides methods of making 4-imino Compounds of theInvention, e.g., any Compound of Formula II, wherein Q is C(═N(R₆)) ashereinbefore described, for example, comprising reacting the Compound ofFormula II, wherein Q is C(═S), with NH₂(R₆) in the presence of HgCl₂,e.g., in a solvent such as THF, and heating the reaction mixture in amicrowave, e.g., to >50° C., e.g., >75° C., e.g., >100° C., for example,in a microwave to about 110° C.

The invention also provides methods of making Compounds of Formula II,wherein Q is CH₂ comprising reacting a Compound of Formula II, wherein Qis C(═O), with a reducing agent, e.g., diisobutylaluminum hydride(DIBAL-H), lithium aluminum hydride, sodium borohydride, preferably,DIBAL-H.

Alternatively, the Compounds of the Invention, e.g., a Compound ofFormula II wherein Q is C(═S), C(═N(R₆)) or CH₂, may be prepared firstbefore attaching on R₁, R₂, R₃ and/or R₄.

The invention thus provides methods of making Compounds of theInvention, wherein Q is C(═O) and the remaining substituents are asdescribed above, for example, comprising

-   -   (i) reacting Intermediate IIIe with a compound of formula R₄OH,        wherein R₄ is as hereinbefore described under basic conditions        with heating, for example wherein the        2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is a compound of        Formula IIIe:

-   -   wherein R₁, R₂ and R₃ are as defined above; and/or    -   (ii) reacting intermediate IIj with a compound of formula L-R₂        wherein L is a leaving group, e.g., halogen, mesylate, or        tosylate, and R₂ is as hereinbefore described, for example        wherein R₂ is isobutyl, N-methylpyrrolidin3-yl, or neopentyl        group, e.g., under basic conditions:

wherein R₁, R₃ and R₄ are as defined above, e.g., with reference toFormula II.Methods of Using Compounds of the Invention

The Compounds of the Invention are useful in the treatment of diseasescharacterized by disruption of or damage to cAMP and cGMP mediatedpathways, e.g., as a result of increased expression of PDE1 or decreasedexpression of cAMP and cGMP due to inhibition or reduced levels ofinducers of cyclic nucleotide synthesis, such as dopamine and nitricoxide (NO). By preventing the degradation of cAMP and cGMP by PDE1B,thereby increasing intracellular levels of cAMP and cGMP, the Compoundsof the Invention potentiate the activity of cyclic nucleotide synthesisinducers.

The invention provides methods of treatment of any one or more of thefollowing conditions:

-   -   (i) Neurodegenerative diseases, including Parkinson's disease,        restless leg tremors, dyskinesias, Huntington's disease,        Alzheimer's disease, and drug-induced movement disorders;    -   (ii) Mental disorders, including depression, attention deficit        disorder, attention deficit hyperactivity disorder, bipolar        illness, anxiety, sleep disorders, e.g., narcolepsy, cognitive        impairment, dementia, Tourette's syndrome, autism, fragile X        syndrome, psychostimulant withdrawal, and drug addiction;    -   (iii) Circulatory and cardiovascular disorders, including        cerebrovascular disease, stroke, congestive heart disease,        hypertension or pulmonary hypertension, and sexual dysfunction;    -   (iv) Respiratory and inflammatory disorders, including asthma,        chronic obstructive pulmonary disease, and allergic rhinitis, as        well as autoimmune and inflammatory diseases;    -   (v) Any disease or condition characterized by low levels of cAMP        and/or cGMP (or inhibition of cAMP and/or cGMP signaling        pathways) in cells expressing PDE1; and/or    -   (vi) Any disease or condition characterized by reduced dopamine        D1 receptor signaling activity,        comprising administering an effective amount of a Compound of        the Invention, e.g., compound according to any of Formulae II,        II(a)-II(f) or 2.1-2.67, in free or pharmaceutically acceptable        salt form, or a composition comprising such a Compound of the        Invention, to a human or animal patient in need thereof. This        method also encompasses administering an effective amount of a        Compound of the Invention in free or pharmaceutically acceptable        salt form. In another aspect, the invention provides a method of        treatment of the conditions disclosed above comprising        administering a therapeutically effective amount of compound        according to any of Formulae II, II(a)-II(f) or 2.1-2.67, in        free or pharmaceutically acceptable salt form, or a composition        comprising the same, to a human or animal patient in need        thereof.

In an especially preferred embodiment, the invention provides methods oftreatment or prophylaxis for narcolepsy. In this embodiment, PDE 1Inhibitors may be used as a sole therapeutic agent, but may also be usedin combination or for co-administration with other active agents. Thus,the invention further comprises a method of treating narcolepsycomprising administering simultaneously, sequentially, orcontemporaneously administering therapeutically effective amounts of

-   -   (i) a PDE 1 Inhibitor of the Invention, e.g., a compound        according to any of Formulae II, II(a)-II(f) or 2.1-2.67; and    -   (ii) a compound to promote wakefulness or regulate sleep, e.g.,        selected from (a) central nervous system stimulants-amphetamines        and amphetamine like compounds, e.g., methylphenidate,        dextroamphetamine, methamphetamine, and pemoline; (b)        modafinil, (c) antidepressants, e.g., tricyclics (including        imipramine, desipramine, clomipramine, and protriptyline) and        selective serotonin reuptake inhibitors (including fluoxetine        and sertraline); and/or (d) gamma hydroxybutyrate (GHB),        in free or pharmaceutically acceptable salt form, to a human or        animal patient in need thereof. In another embodiment, the        invention provides methods of treatment or prophylaxis for        narcolepsy as herein before described, wherein the PDE1        inhibitor is in a form of a pharmaceutical composition.

In another embodiment, the invention further provides methods oftreatment or prophylaxis of a condition which may be alleviated by theenhancement of the progesterone signaling comprising administering aneffective amount of a Compound of the Invention, e.g., any of FormulaeII, II(a)-II(f) or 2.1-2.67, in free or pharmaceutically acceptable saltform. Disease or condition that may be ameliorated by enhancement ofprogesterone signaling include, but are not limited to, female sexualdysfunction, secondary amenorrhea (e.g., exercise amenorrhoea,anovulation, menopause, menopausal symptoms, hypothyroidism),pre-menstrual syndrome, premature labor, infertility, for exampleinfertility due to repeated miscarriage, irregular menstrual cycles,abnormal uterine bleeding, osteoporosis, autoimmmune disease, multiplesclerosis, prostate enlargement, prostate cancer, and hypothyroidism.For example, by enhancing progesterone signaling, the PDE 1 inhibitorsmay be used to encourage egg implantation through effects on the liningof uterus, and to help maintain pregnancy in women who are prone tomiscarriage due to immune response to pregnancy or low progesteronefunction. The novel PDE 1 inhibitors, e.g., as described herein, mayalso be useful to enhance the effectiveness of hormone replacementtherapy, e.g., administered in combination withestrogen/estradiol/estriol and/or progesterone/progestins inpostmenopausal women, and estrogen-induced endometrial hyperplasia andcarcinoma. The methods of the invention are also useful for animalbreeding, for example to induce sexual receptivity and/or estrus in anonhuman female mammal to be bred.

In this embodiment, PDE 1 Inhibitors may be used in the foregoingmethods of treatment or prophylaxis as a sole therapeutic agent, but mayalso be used in combination or for co-administration with other activeagents, for example in conjunction with hormone replacement therapy.Thus, the invention further comprises a method of treating disordersthat may be ameliorated by enhancement of progesterone signalingcomprising administering simultaneously, sequentially, orcontemporaneously administering therapeutically effective amounts of

-   -   (i) a PDE 1 Inhibitor of the Invention, e.g., A Compound of the        Invention, e.g., any of Formulae II, II(a)-II(f) or 2.1-2.67,        and    -   (ii) a hormone, e.g., selected from estrogen and estrogen        analogues (e.g., estradiol, estriol, estradiol esters) and        progesterone and progesterone analogues (e.g., progestins)        in free or pharmaceutically acceptable salt form, to a human or        animal patient in need thereof.

The invention also provides a method for enhancing or potentiatingdopamine D1 intracellular signaling activity in a cell or tissuecomprising contacting said cell or tissue with an amount of a Compoundof the Invention sufficient to inhibit PDE1B activity.

The invention also provides a method for enhancing or potentiatingprogesterone signaling activity in a cell or tissue comprisingcontacting said cell or tissue with an amount of a Compound of theInvention sufficient to inhibit PDE1B activity.

The invention also provides a method for treating a PDE1-related,especially PDE1B-related disorder, a dopamine D1 receptor intracellularsignaling pathway disorder, or disorders that may be alleviated by theenhancement of the progesterone signaling pathway in a patient in needthereof comprising administering to the patient an effective amount of aCompound of the Invention that inhibits PDE1B, wherein PDE1B activitymodulates phosphorylation of DARPP-32 and/or the GluR1 AMPA receptor.

“The Compound of the Invention” referred to above includes any of thecompounds disclosed herein, e.g., a Compound of Formulae II, II(a)-II(f)or 2.1-2.67, in free or pharmaceutically acceptable salt form.

In another aspect, the invention also provides a method for thetreatment for glaucoma or elevated intraocular pressure comprisingtopical administration of a therapeutically effective amount of aphosphodiesterase type I (PDE1) Inhibitor of the Invention, e.g., any ofFormulae II, II(a)-II(f) or 2.1-2.67, in free or pharmaceuticallyacceptable salt form, in an opthalmically compatible carrier to the eyeof a patient in need thereof. However, treatment may alternativelyinclude a systemic therapy. Systemic therapy includes treatment that candirectly reach the bloodstream, or oral methods of administration, forexample.

The invention further provides a pharmaceutical composition for topicalophthalmic use comprising a PDE1 inhibitor; for example an ophthalmicsolution, suspension, cream or ointment comprising a PDE1 Inhibitor ofthe Invention, e.g., a Compound of Formula II, e.g., any of Formulae II,II(a)-II(f) or 2.1-2.67, in free or ophthamalogically acceptable saltform, in combination or association with an ophthamologically acceptablediluent or carrier.

Optionally, the PDE1 inhibitor may be administered sequentially orsimultaneously with a second drug useful for treatment of glaucoma orelevated intraocular pressure. Where two active agents are administered,the therapeutically effective amount of each agent may be below theamount needed for activity as monotherapy. Accordingly, a subthresholdamount (i.e., an amount below the level necessary for efficacy asmonotherapy) may be considered therapeutically effective and also mayalso be referred alternatively as an effective amount. Indeed, anadvantage of administering different agents with different mechanisms ofaction and different side effect profiles may be to reduce the dosageand side effects of either or both agents, as well as to enhance orpotentiate their activity as monotherapy.

The invention thus provides the method of treatment of a conditionselected from glaucoma and elevated intraocular pressure comprisingadministering to a patient in need thereof an effective amount, e.g., asubthreshold amount, of an agent known to lower intraocular pressureconcomitantly, simultaneously or sequentially with an effective amount,e.g., a subthreshold amount, of a PDE1 Inhibitor of the Invention, e.g.,any of Formulae II, II(a)-II(f) or 2.1-2.67, in free or pharmaceuticallyacceptable salt form, such that amount of the agent known to lowerintraocular pressure and the amount of the PDE1 inhibitor in combinationare effective to treat the condition. In one embodiment, one or both ofthe agents are administered topically to the eye. Thus the inventionprovides a method of reducing the side effects of treatment of glaucomaor elevated intraocular pressure by administering a reduced dose of anagent known to lower intraocular pressure concomitantly, simultaneouslyor sequentially with an effective amount of a PDE1 inhibitor. However,methods other than topical administration, such as systemic therapeuticadministration, may also be utilized.

The optional additional agent or agents for use in combination with aPDE1 inhibitor may, for example, be selected from the existing drugscomprise typically of instillation of a prostaglandin, pilocarpine,epinephrine, or topical beta-blocker treatment, e.g. with timolol, aswell as systemically administered inhibitors of carbonic anhydrase, e.g.acetazolamide. Cholinesterase inhibitors such as physostigmine andechothiopate may also be employed and have an effect similar to that ofpilocarpine. Drugs currently used to treat glaucoma thus include, e.g.,

-   -   1. Prostaglandin analogs such as latanoprost (Xalatan),        bimatoprost (Lumigan) and travoprost (Travatan), which increase        uveoscleral outflow of aqueous humor. Bimatoprost also increases        trabecular outflow.    -   2. Topical beta-adrenergic receptor antagonists such as timolol,        levobunolol (Betagan), and betaxolol, which decrease aqueous        humor production by the ciliary body.    -   3. Alpha₂-adrenergic agonists such as brimonidine (Alphagan),        which work by a dual mechanism, decreasing aqueous production        and increasing uveo-scleral outflow.    -   4. Less-selective sympathomimetics like epinephrine and        dipivefrin (Propine) increase outflow of aqueous humor through        trabecular meshwork and possibly through uveoscleral outflow        pathway, probably by a beta₂-agonist action.    -   5. Miotic agents (parasympathomimetics) like pilocarpine work by        contraction of the ciliary muscle, tightening the trabecular        meshwork and allowing increased outflow of the aqueous humour.    -   6. Carbonic anhydrase inhibitors like dorzolamide (Trusopt),        brinzolamide (Azopt), acetazolamide (Diamox) lower secretion of        aqueous humor by inhibiting carbonic anhydrase in the ciliary        body.    -   7. Physostigmine is also used to treat glaucoma and delayed        gastric emptying.

For example, the invention provides pharmaceutical compositionscomprising a PDE1 Inhibitor of the Invention and an agent selected from(i) the prostanoids, unoprostone, latanoprost, travoprost, orbimatoprost; (ii) an alpha adrenergic agonist such as brimonidine,apraclonidine, or dipivefrin and (iii) a muscarinic agonist, such aspilocarpine. For example, the invention provides ophthalmic formulationscomprising a PDE-1 Inhibitor of the Invention together with bimatoprost,abrimonidine, brimonidine, timolol, or combinations thereof, in free orophthamalogically acceptable salt form, in combination or associationwith an ophthamologically acceptable diluent or carrier. In addition toselecting a combination, however, a person of ordinary skill in the artcan select an appropriate selective receptor subtype agonist orantagonist. For example, for alpha adrenergic agonist, one can select anagonist selective for an alpha 1 adrenergic receptor, or an agonistselective for an alpha₂ adrenergic receptor such as brimonidine, forexample. For a beta-adrenergic receptor antagonist, one can select anantagonist selective for either β₁, or β₂, or β₃, depending on theappropriate therapeutic application. One can also select a muscarinicagonist selective for a particular receptor subtype such as M₁-M₅.

The PDE 1 inhibitor may be administered in the form of an ophthalmiccomposition, which includes an ophthalmic solution, cream or ointment.The ophthalmic composition may additionally include anintraocular-pressure lowering agent.

In yet another example, the PDE-1 Inhibitors disclosed may be combinedwith a subthreshold amount of an intraocular pressure-lowering agentwhich may be a bimatoprost ophthalmic solution, a brimonidine tartrateophthalmic solution, or brimonidine tartrate/timolol maleate ophthalmicsolution.

In addition to the above-mentioned methods, it has also beensurprisingly discovered that PDE1 inhibitors are useful to treatpsychosis, for example, any conditions characterized by psychoticsymptoms such as hallucinations, paranoid or bizarre delusions, ordisorganized speech and thinking, e.g., schizophrenia, schizoaffectivedisorder, schizophreniform disorder, psychotic disorder, delusionaldisorder, and mania, such as in acute manic episodes and bipolardisorder. Without intending to be bound by any theory, it is believedthat typical and atypical antipsychotic drugs such as clozapineprimarily have their antagonistic activity at the dopamine D2 receptor.PDE1 inhibitors, however, primarily act to enhance signaling at thedopamine D1 receptor. By enhancing D1 receptor signaling, PDE1inhibitors can increase NMDA receptor function in various brain regions,for example in nucleus accumbens neurons and in the prefrontal cortex.This enhancement of function may be seen for example in NMDA receptorscontaining the NR2B subunit, and may occur e.g., via activation of theSrc and protein kinase A family of kinases.

Therefore, the invention provides a new method for the treatment ofpsychosis, e.g., schizophrenia, schizoaffective disorder,schizophreniform disorder, psychotic disorder, delusional disorder, andmania, such as in acute manic episodes and bipolar disorder, comprisingadministering an effective amount of a phosphodiesterase-1 (PDE1)Inhibitor of the Invention, e.g., any of Formulae II, II(a)-II(f) or2.1-2.67, in free or pharmaceutically acceptable salt form, to a patientin need thereof.

PDE 1 Inhibitors may be used in the foregoing methods of treatmentprophylaxis as a sole therapeutic agent, but may also be used incombination or for co-administration with other active agents. Thus, theinvention further comprises a method of treating psychosis, e.g.,schizophrenia, schizoaffective disorder, schizophreniform disorder,psychotic disorder, delusional disorder, or mania, comprisingadministering simultaneously, sequentially, or contemporaneouslyadministering therapeutically effective amounts of:

-   -   (i) a PDE 1 Inhibitor of the invention, e.g., any of Formulae        II, II(a)-II(f) or 2.1-2.67, in free or pharmaceutically        acceptable salt form; and    -   (ii) an antipsychotic, e.g.,        -   Typical antipsychotics, e.g.,            -   Butyrophenones, e.g. Haloperidol (Haldol, Serenace),                Droperidol (Droleptan);            -   Phenothiazines, e.g., Chlorpromazine (Thorazine,                Largactil), Fluphenazine (Prolixin), Perphenazine                (Trilafon), Prochlorperazine (Compazine), Thioridazine                (Mellaril, Melleril), Trifluoperazine (Stelazine),                Mesoridazine, Periciazine, Promazine, Triflupromazine                (Vesprin), Levomepromazine (Nozinan), Promethazine                (Phenergan), Pimozide (Orap);            -   Thioxanthenes, e.g., Chlorprothixene, Flupenthixol                (Depixol, Fluanxol), Thiothixene (Navane),                Zuclopenthixol (Clopixol, Acuphase);        -   Atypical antipsychotics, e.g.,            -   Clozapine (Clozaril), Olanzapine (Zyprexa), Risperidone                (Risperdal), Quetiapine (Seroquel), Ziprasidone                (Geodon), Amisulpride (Solian), Paliperidone (Invega),                Aripiprazole (Abilify), Bifeprunox; norclozapine,                in free or pharmaceutically acceptable salt form, to a                patient in need thereof.

In a particular embodiment, the Compounds of the Invention areparticularly useful for the treatment or prophylaxis of schizophrenia.

Compounds of the Invention, e.g., any of Formulae II, II(a)-II(f) or2.1-2.67, in free or pharmaceutically acceptable salt form, areparticularly useful for the treatment of Parkinson's disease,schizophrenia, narcolepsy, glaucoma and female sexual dysfunction.

In still another aspect, the invention provides a method of lengtheningor enhancing growth of the eyelashes by administering an effectiveamount of a prostaglandin analogue, e.g., bimatoprost, concomitantly,simultaneously or sequentially with an effective amount of a PDE1inhibitor of the Invention, e.g., a e.g., any of Formulae II,II(a)-II(f) or 2.1-2.67, in free or pharmaceutically acceptable saltform, to the eye of a patient in need thereof.

In yet another aspect, the invention provides a method for the treatmentof traumatic brain injury comprising administering a therapeuticallyeffective amount of a Compound of the Invention, e.g., any of FormulaeII, II(a)-II(f) or 2.1-2.67, in free or pharmaceutically acceptable saltform, to a patient in need thereof. Traumatic brain injury (TBI)encompasses primary injury as well as secondary injury, including bothfocal and diffuse brain injuries. Secondary injuries are multiple,parallel, interacting and interdependent cascades of biologicalreactions arising from discrete subcellular processes (e.g., toxicitydue to reactive oxygen species, overstimulation of glutamate receptors,excessive influx of calcium and inflammatory upregulation) which arecaused or exacerbated by the inflammatory response and progress afterthe initial (primary) injury. Abnormal calcium homeostasis is believedto be a critical component of the progression of secondary injury inboth grey and white matter. For a review of TBI, see Park et al., CMAJ(2008) 178(9):1163-1170, the contents of which are incorporated hereinin their entirety. Studies have shown that the cAMP-PKA signalingcascade is downregulated after TBI and treatment of PDE IV inhibitorssuch as rolipram to raise or restore cAMP level improveshistopathological outcome and decreases inflammation after TBI. AsCompounds of the present invention is a PDE1 inhibitor, it is believedthat these compounds are also useful for the treatment of TBI, e.g., byrestoring cAMP level and/or calcium homeostasis after traumatic braininjury.

The present invention also provides

-   -   (i) a Compound of the Invention for use as a pharmaceutical, for        example for use in any method or in the treatment of any disease        or condition as hereinbefore set forth,    -   (ii) the use of a Compound of the Invention in the manufacture        of a medicament for treating any disease or condition as        hereinbefore set forth,    -   (iii) a pharmaceutical composition comprising a Compound of the        Invention in combination or association with a pharmaceutically        acceptable diluent or carrier, and    -   (iv) a pharmaceutical composition comprising a Compound of the        Invention in combination or association with a pharmaceutically        acceptable diluent or carrier for use in the treatment of any        disease or condition as hereinbefore set forth.

Therefore, the invention provides use of a Compound of the Invention,e.g., any of Formulae II, II(a)-II(f) or 2.1-2.67, in free orpharmaceutically acceptable salt form, for the manufacture of amedicament for the treatment or prophylactic treatment of the followingdiseases: Parkinson's disease, restless leg, tremors, dyskinesias,Huntington's disease, Alzheimer's disease, and drug-induced movementdisorders; depression, attention deficit disorder, attention deficithyperactivity disorder, bipolar illness, anxiety, sleep disorder,narcolepsy, cognitive impairment, dementia, Tourette's syndrome, autism,fragile X syndrome, psychostimulant withdrawal, and/or drug addiction;cerebrovascular disease, stroke, congestive heart disease, hypertension,pulmonary hypertension, and/or sexual dysfunction; asthma, chronicobstructive pulmonary disease, and/or allergic rhinitis, as well asautoimmune and inflammatory diseases; and/or female sexual dysfunction,exercise amenorrhoea, anovulation, menopause, menopausal symptoms,hypothyroidism, pre-menstrual syndrome, premature labor, infertility,irregular menstrual cycles, abnormal uterine bleeding, osteoporosis,multiple sclerosis, prostate enlargement, prostate cancer,hypothyroidism, estrogen-induced endometrial hyperplasia or carcinoma;and/or any disease or condition characterized by low levels of cAMPand/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) incells expressing PDE1, and/or by reduced dopamine D1 receptor signalingactivity; and/or any disease or condition that may be ameliorated by theenhancement of progesterone signaling; comprising administering aneffective amount of a Compound of the Invention, or a pharmaceuticalcomposition comprising a Compound of the Invention, to a patient in needof such treatment.

The invention also provides use of a Compound of the Invention for themanufacture of a medicament for the treatment or prophylactic treatmentof:

-   -   a) glaucoma or elevated intraocular pressure,    -   b) psychosis, for example, any conditions characterized by        psychotic symptoms such as hallucinations, paranoid or bizarre        delusions, or disorganized speech and thinking, e.g.,        schizophrenia, schizoaffective disorder, schizophreniform        disorder, psychotic disorder, delusional disorder, and mania,        such as in acute manic episodes and bipolar disorder, or    -   c) traumatic brain injury.

The invention further provides use of the Compound of the Invention forlengthening or enhancing growth of the eyelashes.

The words “treatment” and “treating” are to be understood accordingly asembracing prophylaxis and treatment or amelioration of symptoms ofdisease as well as treatment of the cause of the disease.

Compounds of the Invention are in particular useful for the treatment ofParkinson's disease, narcolepsy and female sexual dysfunction.

For methods of treatment, the word “effective amount” is intended toencompass a therapeutically effective amount to treat a specific diseaseor disorder.

The term “pulmonary hypertension” is intended to encompass pulmonaryarterial hypertension.

The term “patient” include human or non-human (i.e., animal) patient. Inparticular embodiment, the invention encompasses both human andnonhuman. In another embodiment, the invention encompasses nonhuman. Inother embodiment, the term encompasses human.

The term “comprising” as used in this disclosure is intended to beopen-ended and does not exclude additional, unrecited elements or methodsteps.

Compounds of the Invention may be used as a sole therapeutic agent, butmay also be used in combination or for co-administration with otheractive agents. For example, as Compounds of the Invention potentiate theactivity of D1 agonists, such as dopamine, they may be simultaneously,sequentially, or contemporaneously administered with conventionaldopaminergic medications, such as levodopa and levodopa adjuncts(carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, andanticholinergics, e.g., in the treatment of a patient having Parkinson'sdisease. In addition, the novel PDE 1 inhibitors of the Invention, e.g.,the Compounds of the Invention as described herein, may also beadministered in combination with estrogen/estradiol/estriol and/orprogesterone/progestins to enhance the effectiveness of hormonereplacement therapy or treatment of estrogen-induced endometrialhyperplasia or carcinoma.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular Compound of the Invention used, the mode ofadministration, and the therapy desired. Compounds of the Invention maybe administered by any suitable route, including orally, parenterally,transdermally, or by inhalation, but are preferably administered orally.In general, satisfactory results, e.g. for the treatment of diseases ashereinbefore set forth are indicated to be obtained on oraladministration at dosages of the order from about 0.01 to 2.0 mg/kg. Inlarger mammals, for example humans, an indicated daily dosage for oraladministration will accordingly be in the range of from about 0.75 to150 mg, conveniently administered once, or in divided doses 2 to 4times, daily or in sustained release form. Unit dosage forms for oraladministration thus for example may comprise from about 0.2 to 75 or 150mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a Compound of theInvention, together with a pharmaceutically acceptable diluent orcarrier therefor.

Pharmaceutical compositions comprising Compounds of the Invention may beprepared using conventional diluents or excipients and techniques knownin the galenic art. Thus oral dosage forms may include tablets,capsules, solutions, suspensions and the like.

EXAMPLES

The synthetic methods for various Compounds of the Present Invention areillustrated below. Other compounds of the Invention and their salts maybe made using the methods as similarly described below and/or by methodssimilar to those generally described in the detailed description and bymethods known in the chemical art.

Example 13-(cyclopentyloxy)-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

Step 1)2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(422 mg, 1.2 mmol), isobutyl iodide (276 μL, 2.4 mmol) and potassiumcarbonate (497 mg, 3.6 mmol) are place in a Biotage microwave vial, andthen DMF (6 mL) is added. The mixture is heated in a Biotage microwaveinstrument at 140° C. for 30 min. The mixture is diluted with water (150mL), and then extracted with methylene chloride three times. Thecombined organic phase is evaporated to dryness to give 460 mg of crudeproduct as pale yellow solids, which is used in the next step withoutfurther purification. MS (ESI) m/z 408.2 [M+H]⁺.

Step 2)3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(450 mg, 1.1 mmol) and hexachloroethane (523 mg, 2.2 mmol) are dissolvedin 5 mL of methylene chloride, and then 1.0 M LiHMDS (2.2 mL, 2.2 mmol)in THF is added dropwise. After the reaction mixture is stirred at roomtemperature for 10 min, water is added, and then extracted withmethylene chloride three times. The combined organic phase is evaporatedto dryness to give 520 mg of crude product as off-white solids, which isused in the next step without further purification. MS (ESI) m/z 442.2[M+H]⁺.

Step 3)3-(cyclopentyloxy)-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(20 mg, 0.045 mmol), cesium carbonate (22 mg, 0.068 mmol) andcyclopentanol (0.3 mL) are placed in a Biotage microwave vial. The vialis sealed, and then heated in a Biotage microwave instrument at 150° C.for 4 h. The reaction mixture is purified with a semi-preparative HPLCto give 10.4 mg of pure product as pale yellow solids (Purity: 97.7%).MS (ESI) m/z 492.2 [M+H]⁺.

Example 22-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-3-phenoxy-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(40 mg, 0.095 mmol), potassium carbonate (40 mg, 0.28 mmol) and phenol(26 mg, 0.28 mmol) are placed in a Biotage microwave vial, and then 0.4mL of dioxane is added. The vial is sealed, and then heated in a Biotagemicrowave instrument at 150° C. for 3 h. The reaction mixture is dilutedwith DMF, and then filtered. The filtrate is purified with asemi-preparative HPLC to give 32 mg of pure product as pale yellowcrystals (Purity: 99.9%). MS (ESI) m/z 500.2 [M+H]⁺.

Example 35-methyl-7-neopentyl-3-phenoxy-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

Step 1)5-methyl-7-neopentyl-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

5-methyl-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (236mg, 1.0 mmol), 4-(4-(chloromethyl)phenyl)pyridine (305 mg, 1.5 mmol) andpotassium carbonate (414 mg, 3.0 mmol) are suspensed in 3 mL of DMF. Thereaction mixture is stirred at room temperature overnight, and thendiluted with 100 mL of water. The mixture is extracted with methylenechloride four times (40 mL×4). The combined organic phase is dried overanhydrous sodium sulfate. After filtration, the filtrate is evaporatedto dryness to give 510 mg of crude product, which is used in the nextstep without further purification. MS (ESI) m/z 404.2 [M+H]⁺.

Step 2)3-chloro-5-methyl-7-neopentyl-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

5-methyl-7-neopentyl-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(500 mg, 1.24 mmol) and hexachloroethane (587 mg, 2.48 mmol) aredissolved in 8 mL of methylene chloride, and then 1.0 M LiHMDS (2.48 mL,2.48 mmol) in THF is added dropwise. After the reaction mixture isstirred at room temperature for 10 min, 100 mL of deionized water isadded, and then extracted with methylene chloride four times (30 mL×4).The combined organic phase is dried over anhydrous sodium sulfate. Afterfiltration, the filtrate is evaporated to dryness to give 500 mg ofcrude product as brown solids, which is used in the next step withoutfurther purification. MS (ESI) m/z 438.2 [M+H]⁺.

Step 3)5-methyl-7-neopentyl-3-phenoxy-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

3-chloro-5-methyl-7-neopentyl-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(30 mg, 0.069 mmol), potassium carbonate (29 mg, 0.2 mmol) and phenol(20 mg, 0.20 mmol) are placed in a Biotage microwave vial, and then 0.3mL of dioxane is added. The vial is sealed, and then heated in a Biotagemicrowave instrument at 150° C. for 3 h. The reaction mixture is dilutedwith DMF, and then filtered. The filtrate is purified with asemi-preparative HPLC to give 23 mg of pure product as pale yellowsolids. MS (ESI) m/z 496.2 [M+H]⁺.

Example 45-methyl-7-neopentyl-3-propoxy-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

The synthesis method is analogous to Example 3 wherein n-propanol isadded in step 3 instead of phenol. MS (ESI) m/z 462.3 [M+H]⁺.

Example 5 Measurement of PDE1B Inhibition In Vitro Using IMAPPhosphodiesterase Assay Kit

Phosphodiesterase 1B (PDE1B) is a calcium/calmodulin dependentphosphodiesterase enzyme that converts cyclic guanosine monophosphate(cGMP) to 5′-guanosine monophosphate (5′-GMP). PDE1B can also convert amodified cGMP substrate, such as the fluorescent moleculecGMP-fluorescein, to the corresponding GMP-fluorescein. The generationof GMP-fluorescein from cGMP-fluorescein can be quantitated, using, forexample, the IMAP (Molecular Devices, Sunnyvale, Calif.)immobilized-metal affinity particle reagent.

Briefly, the IMAP reagent binds with high affinity to the free5′-phosphate that is found in GMP-fluorescein and not incGMP-fluorescein. The resulting GMP-fluorescein—IMAP complex is largerelative to cGMP-fluorescein. Small fluorophores that are bound up in alarge, slowly tumbling, complex can be distinguished from unboundfluorophores, because the photons emitted as they fluoresce retain thesame polarity as the photons used to excite the fluorescence.

In the phosphodiesterase assay, cGMP-fluorescein, which cannot be boundto IMAP, and therefore retains little fluorescence polarization, isconverted to GMP-fluorescein, which, when bound to IMAP, yields a largeincrease in fluorescence polarization (Δmp). Inhibition ofphosphodiesterase, therefore, is detected as a decrease in Δmp.

Enzyme Assay

Materials: All chemicals are available from Sigma-Aldrich (St. Louis,Mo.) except for IMAP reagents (reaction buffer, binding buffer, FL-GMPand IMAP beads), which are available from Molecular Devices (Sunnyvale,Calif.).

Assay: 3′,5′-cyclic-nucleotide-specific bovine brain phosphodiesterase(Sigma, St. Louis, Mo.) is reconstituted with 50% glycerol to 2.5 U/ml.One unit of enzyme will hydrolyze 1.0 mole of 3′,5′-cAMP to 5′-AMP permin at pH 7.5 at 30° C. One part enzyme is added to 1999 parts reactionbuffer (30 M CaCl₂, 10 U/ml of calmodulin (Sigma P2277), 10 mM Tris-HClpH 7.2, 10 mM MgCl₂, 0.1% BSA, 0.05% NaN₃) to yield a finalconcentration of 1.25 mU/ml. 99 μl of diluted enzyme solution is addedinto each well in a flat bottom 96-well polystyrene plate to which 1 μlof test compound dissolved in 100% DMSO is added. The compounds aremixed and pre-incubated with the enzyme for 10 min at room temperature.

The FL-GMP conversion reaction is initiated by combining 4 parts enzymeand inhibitor mix with 1 part substrate solution (0.225 μM) in a384-well microtiter plate. The reaction is incubated in dark at roomtemperature for 15 min. The reaction is halted by addition of 60 μl ofbinding reagent (1:400 dilution of IMAP beads in binding buffersupplemented with 1:1800 dilution of antifoam) to each well of the384-well plate. The plate is incubated at room temperature for 1 hour toallow IMAP binding to proceed to completion, and then placed in anEnvision multimode microplate reader (PerkinElmer, Shelton, Conn.) tomeasure the fluorescence polarization (Δmp).

A decrease in GMP concentration, measured as decreased Δmp, isindicative of inhibition of PDE activity. IC₅₀ values are determined bymeasuring enzyme activity in the presence of 8 to 16 concentrations ofcompound ranging from 0.0037 nM to 80,000 nM and then plotting drugconcentration versus ΔmP, which allows IC₅₀ values to be estimated usingnonlinear regression software (XLFit; IDBS, Cambridge, Mass.).

The Compounds of the Invention may be selected and tested in this assayto show PDE1 inhibitory activity. Exemplified compounds are shown tohave IC₅₀ activities of less than 100 μM, in some instances less than100 nM, e.g., in some instances, less than 25 nM, in other instances,less than 10 nM.

Example 6 PDE1 Inhibitor Effect on Sexual Response in Female Rats

The effect of PDE1 inhibitors on Lordosis Response in female rats may bemeasured as described in Mani, et al., Science (2000) 287: 1053.Ovariectomized and cannulated wild-type rats are primed with 2 μgestrogen followed 24 hours later by intracerebroventricular (icv)injection of progesterone (2 μg), PDE1 inhibitors of the presentinvention (0.1 mg, 1.0 mg or 2.5 mg) or sesame oil vehicle (control).The rats are tested for lordosis response in the presence of male rats.Lordosis response is quantified by the lordosis quotient (LQ=number oflordosis/10 mounts×100). The LQ for estrogen-primed female ratsreceiving Compounds of the Invention, at 0.1 mg, are expected to besimilar to estrogen-primed rats receiving progesterone and higher thanfor estrogen-primed rats receiving vehicle.

What is claimed is:
 1. A compound of Formula II:

wherein (i) Q is —C(═O)—, —C(═S)—, (ii) R₁ is C₁₋₆alkyl; (iii) R₂ isC₁₋₆alkyl wherein said alkyl group is optionally substituted with one ormore halo or hydroxy; (iv) R₃ is 1) attached to one of the nitrogens onthe pyrazolo portion of Formula II and is a moiety of Formula A

wherein: X, Y and Z are, independently, N or C, R₈, R₉, R₁₁ and R₁₂ areindependently H or halogen; and R₁₀ is  aryl or heteroaryl,  whereinsaid aryl, heteroaryl, is optionally substituted with one or moreC₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxy, carboxy, —SH, or anadditional aryl or heteroaryl; provided that when X, Y or Z is nitrogen,R₈, R₉ or R₁₀, respectively, is not present; (v) R₄ is: C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈heterocycloalkyl, —C₀₋₆alkylaryl orC₀₋₆alkylheteroaryl wherein said aryl or heteroaryl is optionallysubstituted with one or more halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy oranother aryl group; in free or salt form, provided that said compound isnot: (a)7-[(2,4-dichlorophenyl)methyl]-3-ethoxy-2,5-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;(b)7-[(4-chlorophenyl)methyl]-3-ethoxy-2,5-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;(c)2-[(2,5-dichlorophenyl)methyl]-3-ethoxy-5,7-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;(d)2-[(4-bromophenyl)methyl]-3-ethoxy-5,7-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;(e)3-[(4-methoxyphenyl)methoxy]-2,5,7-trimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;(f)1-[(3-bromophenyl)methyl]-5,7-dimethyl-3-(2-propen-1-yloxy)-1H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione.2. The compound according to claim 1, which compound is selected fromany one of the following: A) a Compound of Formula II(a):

wherein (i) Q is —C(═O)—, —C(═S)—, (ii) R₁ is C₁₋₆alkyl; (iii) R₂ isC₁₋₆alkyl wherein said alkyl group is optionally substituted with one ormore halo or hydroxy, (iv) R₃ is attached to one of the nitrogens on thepyrazolo portion of Formula II(a) and is a moiety of Formula A

wherein: X, Y and Z are, independently, N or C, R₈, R₉, R₁₁ and R₁₂ areindependently H or halogen; and R₁₀ is aryl or heteroaryl, wherein saidaryl, heteroaryl, is optionally substituted with one or more C₁₋₆alkyl,halogen, haloC₁₋₆alkyl, hydroxy, carboxy, —SH or an additional aryl orheteroaryl, C₁₋₆alkyl sulfonyl; provided that when X, Y or Z isnitrogen, R₈, R₉ or R₁₀, respectively, is not present; (v) R₄ is:C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈heterocycloalkyl, —C₀₋₆alkylaryl or—C₀₋₆alkylheteroaryl wherein said aryl or heteroaryl is optionallysubstituted with one or more halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy oranother aryl group; in free or salt form; B) a Compound of formulaII(b):

wherein: (i) Q is —C(═O)—, —C(═S)—; (ii) R₁ is C₁₋₆alkyl; (iii) R₂ isC₁₋₆alkyl wherein said alkyl group is optionally substituted with one ormore halo or hydroxy, (iv) R₃ is attached to one of the nitrogens on thepyrazolo portion of Formula II(b) and is a moiety of Formula A

wherein: X, Y and Z are, independently, N or C, R₈, R₉, R₁₁ and R₁₂ areindependently H or halogen; and R₁₀ is phenyl, or pyridyl optionallysubstituted with one or more C₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxy,carboxy, —SH or an additional aryl or; provided that when X, Y or Z isnitrogen, R₈, R₉ or R₁₀, respectively, is not present; (v) R₄ is:C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈heterocycloalkyl, —C₀₋₆alkylaryl or—C₀₋₆alkylheteroaryl wherein said aryl or heteroaryl is optionallysubstituted with one or more halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy oranother aryl group; in free or salt form; C) a Compound of FormulaII(c):

wherein: (i) Q is —C(═O)—, —C(═S)—; (ii) R₁ is C₁₋₆alkyl; (iii) R₂ isC₁₋₆alkyl wherein said alkyl group is optionally substituted with one ormore halo or hydroxy, (iv) R₃ is attached to one of the nitrogens on thepyrazolo portion of Formula II(c) and is a moiety of Formula A

wherein: X, Y and Z are, independently, N or C, R₈, R₉, R₁₁ and R₁₂ areindependently H or halogen; and R₁₀ is phenyl, or pyridyl optionallysubstituted with one or more C₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxy,carboxy, —SH or an additional aryl or heteroaryl; provided that when X,Y or Z is nitrogen, R₈, R₉ or R₁₀, respectively, is not present; (v) R₄is: —C₀₋₆alkylaryl or —C₀₋₆alkylheteroaryl wherein said aryl orheteroaryl is optionally substituted with one or more halo, hydroxy,C₁₋₆alkyl C₁₋₆alkoxy or another aryl group; in free or salt form; D) aCompound of Formula II(d):

wherein: (i) Q is —C(═O)—, —C(═S)—; (ii) R₁ is C₁₋₆alkyl; (iii) R₂ isC₁₋₆alkyl wherein said alkyl group is optionally substituted with one ormore halo or hydroxy, (iv) R₃ is attached to one of the nitrogens on thepyrazolo portion of Formula II(d) and is a moiety of Formula A

wherein: X, Y and Z are independently, N or C, R₈, R₉, R₁₁ and R₁₂ areindependently H or halogen; and R₁₀ is phenyl, or pyridyl optionallysubstituted with one or more C₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxy,carboxy, —SH or an additional aryl or heteroaryl; provided that when X,Y or Z is nitrogen, R₈, R₉ or R₁₀, respectively, is not present; (v) R₄is: C₃₋₈cycloalkyl, C₃₋₈heterocycloalkyl, —C₀₋₆alkylaryl or—C₀₋₆alkylheteroaryl wherein said aryl or heteroaryl is optionallysubstituted with one or more halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy oranother aryl group; in free or salt form, E) a Compound of FormulaII(e):

wherein: (i) Q is —C(═O)—, —C(═S)—; (ii) R₁ is C₁₋₆alkyl; (iii) R₂ isC₁₋₆alkyl wherein said alkyl group is optionally substituted with one ormore halo or hydroxy, (iv) R₃ is attached to one of the nitrogens on thepyrazolo portion of Formula II(e) and is a moiety of Formula A

wherein: X, Y and Z are, independently, N or C, R₈, R₉, R₁₁ and R₁₂ areindependently H or halogen; and R₁₀ is phenyl, or pyridyl optionallysubstituted with one or more C₁₋₆alkyl or halogen; provided that when X,Y or Z is nitrogen, R₈, R₉ or R₁₀, respectively, is not present; (v) R₄is phenyl optionally substituted with one or more halo, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy or another aryl group; in free or salt form; F) aCompound of Formula II(f):

wherein: (i) Q is —C(═O)—; (ii) R₁ is C₁₋₆alkyl; (iii) R₂ is C₁₋₆alkyl;(iv) R₃ is attached to one of the nitrogens on the pyrazolo portion ofFormula II(f) and is a moiety of Formula A

wherein: X, Y and Z are C; R₈, R₉, R₁₁ and R₁₂ are H; and R₁₀ ispyridyl, optionally substituted with one or more halogen; (v) R₄ isphenyl optionally substituted with one or more halo, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy or another aryl group; C₁₋₆alkyl, C₃₋₈ cycloalkyl, in free orsalt form.
 3. The compound according to claim 1, wherein Q is —C(═O) infree or salt form.
 4. The compound according to claim 1, wherein R₂ isC₁₋₆alkyl, and wherein the C₁₋₆alkyl is not substituted, in free or saltform.
 5. The compound according to claim 1 wherein R₄ is phenyl orcyclopentyl in free or salt form.
 6. The compound according to claim 1,wherein said compound is selected from any of the following:

in free or salt form.
 7. The compound according to claim 1, wherein saidcompound is:

in free or salt form.
 8. A pharmaceutical composition comprising acompound of Formula II:

wherein (i) Q is —C(═O)—, —C(═S)—; (ii) R₁ is C₁₋₆alkyl; (iii) R₂ isC₁₋₆alkyl wherein said alkyl group is optionally substituted with one ormore halo or hydroxy, (iv) R₃ is 1) attached to one of the nitrogens onthe pyrazolo portion of Formula II and is a moiety of Formula A

wherein: X, Y and Z are independently, N or C, R₈, R₉, R₁₁ and R₁₂ areindependently H or halogen; and R₁₀ is  aryl or heteroaryl,  whereinsaid aryl, heteroaryl, is optionally substituted with one or moreC₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxy, carboxy, —SH, or anadditional aryl or heteroaryl, provided that when X, Y or Z is nitrogen,R₈, R₉ or R₁₀, respectively, is not present; (v) R₄ is: C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈ heterocycloalkyl, —C₀₋₆alkylaryl or—C₀₋₆alkylheteroaryl, wherein said aryl or heteroaryl is optionallysubstituted with one or more halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy oranother aryl group; in free or pharmaceutically acceptable salt form, inadmixture with a pharmaceutically acceptable diluent or carrier.
 9. Apharmaceutical composition for topical ophthalmic use comprising acomposition according to claim 8 in combination or association with anophthamologically acceptable diluents or carrier.
 10. A method for thetreatment of any of the following conditions: Parkinson's disease,restless leg, tremors, dyskinesias, Huntington's disease, Alzheimer'sdisease, and drug-induced movement disorders; depression, attentiondeficit disorder, attention deficit hyperactivity disorder, bipolarillness, anxiety, sleep disorder, narcolepsy, cognitive impairment,dementia, Tourette's syndrome, autism, fragile X syndrome,psychostimulant withdrawal, and/or drug addiction; cerebrovasculardisease, stroke, congestive heart disease, hypertension, pulmonaryhypertension, and/or sexual dysfunction; asthma, chronic obstructivepulmonary disease, and/or allergic rhinitis; and/or female sexualdysfunction, exercise amenorrhoea, anovulation, menopause, menopausalsymptoms, hypothyroidism, pre-menstrual syndrome, premature labor,infertility, irregular menstrual cycles, abnormal uterine bleeding,osteoporosis, multiple sclerosis, prostate enlargement, prostate cancer,estrogen-induced endometrial hyperplasia or carcinoma comprisingadministering a therapeutically effective amount of a compositionaccording to claim 7, to a patient in need of such treatment.
 11. Themethod of claim 10, wherein the condition is Parkinson's disease. 12.The method of claim 10, wherein the condition is cognitive impairment.13. The method of claim 10, wherein the condition is narcolepsy.
 14. Themethod of claim 13 further comprising administering a compound orcompounds selected from central nervous system stimulants, modafinil,antidepressants, and gamma hydroxybutyrate, to a patient in needthereof.
 15. The method of claim 10, wherein said condition is femalesexual dysfunction.
 16. The method of claim 15, further comprisingadministering a compound or compounds selected from a group consistingof estradiol, estriol, estradiol esters, progesterone and progestins toa patient in need thereof.
 17. A method for the treatment for glaucomaor elevated intraocular pressure comprising topical administration of atherapeutically effective amount of a composition according to claim 8to a patient in need of such treatment.
 18. A method for the treatmentof psychosis including schizophrenia, schizoaffective disorder,schizophreniform disorder, psychotic disorder, delusional disorder, andmania, such as in acute manic episodes and bipolar disorder, comprisingadministering an effective amount of a composition according to claim 8.